CN103403004B - As the Pyrrolopyrazine-spirocyclic piperidine acid amides of ion channel modulators - Google Patents

As the Pyrrolopyrazine-spirocyclic piperidine acid amides of ion channel modulators Download PDF

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CN103403004B
CN103403004B CN201280011207.8A CN201280011207A CN103403004B CN 103403004 B CN103403004 B CN 103403004B CN 201280011207 A CN201280011207 A CN 201280011207A CN 103403004 B CN103403004 B CN 103403004B
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pain
compound
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ring
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CN103403004A (en
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S·S·哈迪达鲁阿
E·A·卡莱尔
M·T·米勒
V·阿勒穆加姆
J·麦卡特尼
C·安德森
P·D·J·格鲁坦辉斯
L·江
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Vertex Pharmaceuticals Inc
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Abstract

The present invention relates to the Pyrrolopyrazine as inhibitors of ion channels-spirocyclic piperidine amide compound. What the present invention also provided the compound comprising the present invention can medicinal compositions and use said composition to treat the method for various illness.

Description

As the Pyrrolopyrazine-spirocyclic piperidine acid amides of ion channel modulators
The cross reference of related application
This application claims the U.S. Provisional Patent Application sequence number 61/438 submitted on February 2nd, 2011,685,61/440 submitted on February 9th, 2011, whole contents of all applications are incorporated to herein as a reference by the right of priority of 61/495,538 submitted in the right of priority of 987 and on June 10th, 2011.
Technical field
The present invention relates to the compound as inhibitors of ion channels. The present invention go back providing package containing the compounds of this invention can medicinal compositions, and use said composition treatment various disease conditions method.
Background technology
Pain is a kind of protection mechanism, and it makes the further damage that healthy animal avoids tissue injury and prevent wounded tissue. But, in many cases, pain lasts to no longer including use, or patient will benefit from pain suppress. It is believed that voltage-gated sodium channels plays keying action in pain signal conducts. This conviction is based on the known action of these passages in normal physiologic, pathologic state caused by sodium channel gene suddenlys change, effect before clinical in disease animal model, and clinical availability (Cummins, the T.R. of known sodium channel modulators, Sheets, P.L., andWaxman, S.G., Therolesofsodiumchannelsinnociception:Implicationsformec hanismsofpain.Pain131 (3), 243 (2007); England, S., Voltage-gatedsodiumchannels:thesearchforsubtype-selectiv eanalgesics.ExpertOpinInvestigDrugs17 (12), 1849 (2008); Krafte, D.S.andBannon, A.W., Sodiumchannelsandnociception:recentconceptsandtherapeuti copportunities.CurrOpinPharmacol8 (1), 50 (2008)).
Voltage-gated sodium channels (NaV) is the crucial biological media of electrical signal conduction. NaV be many excitable cell types (such as neurone, skeletal muscle cell, myocardial cell) the main medium of rapid increase stroke of action potential, and be therefore the key (Hille that in those cells, intracellular signaling is initial, Bertil, IonChannelsofExcitableMembranes, Thirded. (SinauerAssociates, Inc., Sunderland, MA, 2001)). Owing to NaV is at conduct initial of neuron signal and institute's role in propagating, the antagonist therefore reducing NaV electric current is possible to prevent or reduces Neurotransmission. Therefore, NaV passage is probably considered to the target spot of pathological conditions, and wherein prediction reduces excitability and can alleviate clinical symptom, such as pain, epilepsy and some irregular pulse (Chahine, M., Chatelier, A., Babich, O., andKrupp, J.J., Voltage-gatedsodiumchannelsinneurologicaldisorders.CNSNe urolDisordDrugTargets7 (2), 144 (2008)).
The Zijia race of NaV coating-forming voltage gated ion channel superfamily, and comprise 9 kinds of isoforms, it is called NaV1.1-NaV1.9. The tissue positioned of these 9 kinds of isoforms is greatly different. NaV1.4 is the main sodium channel of skeletal muscle, and NaV1.5 is the main sodium channel of myocardial cell. NaV1.7,1.8 and 1.9 is mainly positioned at peripheral nervous system, and NaV1.1,1.2,1.3 and 1.6 are at the neuronal pathways seen in axoneure and peripheral nervous system. The behaviour of nine kinds of isoforms is similar, but its voltage-dependent (Catterall different from the specificity of dynamic behavior, W.A., Goldin, A.L., and Waxman, S.G., InternationalUnionofPharmacology.XLVII.Nomenclatureandst ructure-functionrelationshipsofvoltage-gatedsodiumchanne ls.PharmacolRev57 (4), 397 (2005)).
NaV passage has been confirmed as the major target (Cummins of some clinical useful medicaments alleviating pain, T.R., Sheets, P.L., andWaxman, S.G., Therolesofsodiumchannelsinnociception:Implicationsformec hanismsofpain.Pain131 (3), 243 (2007)). Local anesthetic such as lignocaine is by suppressing NaV carrier frequency channel break pain. The local pain that these compounds provide good alleviates, but has the shortcoming eliminating normal acute pain and sensation input. These compounds of Formulations for systemic administration cause dose limitation side effect, its generally owing to neural channel in CNS blocking-up (feel sick, calmness, confusion of consciousness, ataxia). Cardiac side effects can also occurring, and in fact these compounds are also used as 1 class anti-arrhythmic, supposition may be owing in heart, NaV1.5 passage is blocked. Other compound having confirmed effectively to alleviate pain also shows to be blocked by sodium channel to work, comprise Carbamzepine, lamotrigine and tricyclics (Soderpalm, B., Anticonvulsants:aspectsoftheirmechanismsofaction.EurJPai n6SupplA, 3 (2002); Wang, G.K., Mitchell, J., andWang, S.Y., BlockofpersistentlateNa+currentsbyantidepressantsertrali neandparoxetine.JMembrBiol222 (2), 79 (2008)). These compounds are similar to the side effect using local anesthetic to see equally and dosage is limited. Expect that only specific inhibition has effect of increase for the antagonist of the very important isoform of nociception, the minimizing of the side effect caused because of (off-target) passage that misses the target by blocking-up should be able to realize higher dosage administration, and therefore blocks target passage isoform more completely.
Having pointed out four kinds of NaV isoforms especially, NaV1.3,1.7,1.8 and 1.9 are possible pain target spots. In the mankind and rodent, NaV1.3 is mostly just present in the pain perception neurone growing early stage dorsal root ganglion (DRG), and loses soon after birth. NaV1.3 passage is caused to return in DRG neurone however, it has been discovered that damage neural damage, and this can contribute to the allodynic intracellular signaling of the various chronic pain disorders caused due to nerve injury (neuropathic pain). These data have pointed out the drugs block of NaV1.3 may be effective treatment of neuropathic pain. Contrary with this viewpoint, in the mouse model of neuropathic pain, comprehensive gene knockout of NaV1.3 in mouse can not be stoped the development (Nassar of allodynia, M.A.etal., NerveinjuryinducesrobustallodyniaandectopicdischargesinN aV1.3nullmutantmice.MolPain2,33 (2006)). Whether the compensation change of other passage allows the normal neuronal pain of NaV1.3 rejecting mouse still unknown, but the rejecting having reported NaV1.1 can cause the sharply rise of NaV1.3. The retroaction that NaV1.3 rejects can explain these results.
NaV1.7,1.8 and 1.9 expresses at DRG neurone camber, comprises the neurone that aixs cylinder forms C-fiber and A �� nerve fiber, and described C-fiber and A �� nerve fiber are considered to the most of pain signal being loaded with from nociception end to nervus centralis. Being similar to NaV1.3, after nerve injury, the expression of NaV1.7 increases, and can cause neuropathic pain situation. The location of NaV1.7,1.8 and 1.9 in nociceptor causes reducing the hypothesis that may alleviate pain through the sodium current of these passages. In fact, the specific intervention of the level reducing these passages confirms effectively in animal models of pain.
By multiple different technologies specific reduce the behavior that NaV1.7 in rodent can cause can observing in animal pattern pain and reduce. Injecting virus antisense NaV1.7cDNA construct can reduce the normal pain reaction (Yeomans caused by inflammation or mechanical injuries greatly, D.C.etal., Decreaseininflammatoryhyperalgesiabyherpesvector-mediate dknockdownofNaV1.7sodiumchannelsinprimaryafferents.HumGe neTher16 (2), 271 (2005)). Equally, in mouse model, the gene knockout of NaV1.7 in nociceptor neurone subgroup can be reduced acute and inflammatory pain (Nassar, M.A.etal., Nociceptor-specificgenedeletionrevealsamajorroleforNaV1. 7 (PN1) inacuteandinflammatorypain.ProcNatlAcadSciUSA101 (34), 12706 (2004)). Comprehensive rejecting of NaV1.7 in mouse is caused animal death in first day after birth. These mouse cannot be taken food and this is the cause of death speculated.
The treatment reducing NaV1.8 passage in rodent models reduces pain sensitivity specificly effectively. Block NaV1.8 in rat by intrathecal injection oligomeric deoxynucleotide and can reduce neuropathic pain behavior, and make acute pain feel intact (Lai, J.etal., Inhibitionofneuropathicpainbydecreasedexpressionofthetet rodotoxin-resistantsodiumchannel, NaV1.8.Pain95 (1-2), 143 (2002); Porreca, F.etal., Acomparisonofthepotentialroleofthetetrodotoxin-insensiti vesodiumchannels, PN3/SNSandNaN/SNS2, inratmodelsofchronicpain.ProcNatlAcadSciUSA96 (14), 7640 (1999)). In mouse, comprehensive gene knockout of NaV1.8 or the specific destruction of expressing neuronic NaV1.8 greatly reduce the sensation (Akopian of acute mechanicalness, inflammatory and visceral pain, A.N.etal., Thetetrodotoxin-resistantsodiumchannelSNShasaspecialized functioninpainpathways.NatNeurosci2 (6), 541 (1999); Abrahamsen, B.etal., Thecellandmolecularbasisofmechanical, cold, andinflammatorypain.Science321 (5889), 702 (2008); Laird, J.M., Souslova, V., Wood, J.N., andCervero, F., DeficitsinvisceralpainandreferredhyperalgesiainNaV1.8 (SNS/PN3)-nullmice.JNeurosci22 (19), 8352 (2002)). Compared with the antisense test carried out in rats, gene knockout mice seems usually to produce neuropathic pain behavior (Lai after nerve injury, J.etal., Inhibitionofneuropathicpainbydecreasedexpressionofthetet rodotoxin-resistantsodiumchannel, NaV1.8.Pain95 (1-2), 143 (2002); Akopian, A.N.etal., Thetetrodotoxin-resistantsodiumchannelSNShasaspecialized functioninpainpathWays.NatNeurosci2 (6), 541 (1999); Abrahamsen, B.etal., Thecellandmolecularbasisofmechanical, cold, andinflammatorypain.Science321 (5889), 702 (2008); Laird, J.M., SousloVa, V., Wood, J.N., andCervero, F., DeficitsinVisceralpainandreferredhyperalgesiainNaV1.8 (SNS/PN3)-nullmice.JNeurosci22 (19), 8352 (2002)).
The susceptibility of the pain of inflammation-induced is reduced by the comprehensive gene knockout mice of NaV1.9, but still there is normally acute and neuropathic pain behavior (Amaya, F.etal., Thevoltage-gatedsodiumchannelNa (V) 1.9isaneffectorofperipheralinflammatorypainhypersensitiV ity.JNeurosci26 (50), 12852 (2006); Priest, B.T.etal., Contributionofthetetrodotoxin-resistantvoltage-gatedsodi umchannelNaV1.9tosensorytransmissionandnociceptivebehavi or.ProcNatlAcadSciUSA102 (26), 9382 (2005)). Vertebra blocks NaV1.9 and the Pain behaviour of rat is not significantly acted on (Porreca, F.etal., Acomparisonofthepotentialroleofthetetrodotoxin-insensiti vesodiumchannels, PN3/SNSandNaN/SNS2, inratmodelsofchronicpain.ProcNatlAcadSciUSA96 (14), 7640 (1999)).
NaV passage is greatly developed NaV1.1andNaV1.2mutationsresultinvariousformsofepilepsy (Fujiwara by finding and analyze naturally occurring human mutant in the understanding of the special effect of Human physiology and pathology, T., ClinicalspectrumofmutationsinSCN1Agene:severemyoclonicep ilepsyininfancyandrelatedepilepsies.EpilepsyRes70 increases in 1, S223 (2006); George, A.L., Jr., Inheriteddisordersofvoltage-gatedsodiumchannels.JClinInv est115 (8), 1990 (2005); Misra, S.N., Kahlig, K.M., andGeorge, A.L., Jr., ImpairedNaV1.2functionandredueedcellsurfaceexpressioninb enignfamilialneonatal-infantileseizures.Epilepsia49 (9), 1535 (2008)). The sudden change of NaV1.4 causes the muscle illness (Vicart of similar myotonia congenita, S., Sternberg, D., Fontaine, B., andMeola, G., Humanskeletalmusclesodiumchannelopathies.NeurolSci26 (4), 194 (2005)). NaV1.5 sudden change causes the heart abnormality (Bennett of similar Brugada syndrome and long QT syndrome, P.B., Yazawa, K., Makita, N., andGeorge, A.L., Jr., Molecularmechanismforaninheritedcardiacarrhythmia.Nature 376 (6542), 683 (1995); Darbar, D.etal., Cardiacsodiumchannel (SCN5A) variantsassociatedwithatrialfibrillation.Circulation117 (15), 1927 (2008); Wang, Q.etal., SCN5Amutationsassociatedwithaninheritedcardiacarrhythmia, longQTsyndrome.Cell80 (5), 805 (1995)).
The sudden change that latest find has confirmed to encode the gene (SCN9A) of NaV1.7 passage can cause pain to strengthen and pain minimizing syndrome. Waxman group and other people research have differentiated at least 15 kinds of sudden changes, and it causes through the intensifying current of NaV1.7 and relevant with main idiopathic pain syndrome. The sudden change of the threshold value reducing NaV1.7 activation causes heredity erythromelalgia (IEM). IEM patient shows the abnormal cusalgia of its brothers. The normal sudden change not activating character of interference NaV1.7 causes long-time sodium current, and causes paroxysmal severe pain disease (PEPD). PEPD patient shows as near the eyes, lower jaw week (perimandibular) and rectal pain symptom, this symptom is developing (Drenth in whole vital process, J.P.etal., SCN9Amutationsdefineprimaryerythermalgiaasaneuropathicdi sorderofvoltagegatedsodiumchannels.JInvestDermatol124 (6), 1333 (2005); Estacion, M.etal., NaV1.7gain-of-functionmutationsasacontinuum:A1632Edispla ysphysiologicalchangesassociatedwitherythromelalgiaandpa roxysmalextremepaindisordermutationsandproducessymptomso fbothdisorders.JNeurosci28 (43), 11079 (2008)).
Recently, some groups describe NaV1.7 null mutation (Ahmad in human patients, S.etal., AstopcodonmutationinSCN9Acauseslackofpainsensation.HumMo lGenet16 (17), 2114 (2007), Cox, J.J.etal., AnSCN9Achannelopathycausescongenitalinabilitytoexperienc epain.Nature444 (7121), 894 (2006), Goldberg, Y.P.etal., Loss-of-functionmutationsintheNaV1.7geneunderliecongenit alindifferencetopaininmultiplehumanpopulations.ClinGenet 71 (4), 311 (2007)). in all cases, what patient all demonstrated pain is congenital indifferent. these patients report does not under any circumstance all have pain. in these patients, many meetings suffer fearful damage in early days in childhood, because it can't have the protectiveness normal pain contributing to preventing tissue injury and producing suitable protection behavior. significantly lose except the pain sensation and reduce with sense of smell or (Goldberg except not existing, Y.P.etal., Loss-of-functionmutationsintheNaV1.7geneunderliecongenit alindifferencetopaininmultiplehumanpopulations.ClinGenet 71 (4), 311 (2007)), these patients seem completely normal. although NaV1.7 is usually at sympathetic neuron (Toledo-Aral, J.J.etal., IdentificationofPN1, apredominantvoltage-dependentsodiumchannelexpressedprinc ipallyinperipheralneurons.ProcNatlAcadSciUSA94 (4), 1527 (1997)) and adrenal pheochromocytoma (Klugbauer, N., Lacinova, L., Flockerzi, V., andHofmann, F., Structureandfunctionalexpressionofanewmemberofthetetrodo toxin-sensitivevoltage-activatedsodiumchannelfamilyfromh umanneuroendocrinecells.EMBOJ14 (6), 1084 (1995)) high expression level in, these NaV1.7 refractory patient do not demonstrate neuroendocrine or the sign of sympathetic nerve function exception.
The combination of the loss of the acquisition of the NaV1.7 function mutation of pain and the NaV1.7 function mutation of eliminate pain is caused to provide the strong evidence of NaV1.7 its vital role in people's pain signal conducts. Excision tolerance in these patients of the relative good health situation instruction NaV1.7 of NaV1.7-refractory patient is good.
Regrettable, the sodium channel blockers used at present for effect of above-mentioned disease condition to a great extent by the restriction of many side effects. It is disorderly that these side effects comprise various CNS, such as blurred vision, dizzy, nauseating and calm, and more potential irregular pulse and the heart failure threatening life. Therefore, still need to develop other Na channel antagonists, it is preferable that there is higher effect and the antagonist of less side effect.
Summary of the invention
Have now found that the present invention of the present invention and voltage-gated sodium channel inhibitor can be used as by medicinal compositions. These compounds have general formula I:
Or its pharmacologically acceptable salt.
These compounds and following various disease can be used for the treatment of by medicinal compositions, disorderly or illness or alleviate its severity: comprise, but it is not limited to acute, chronic, nervosa or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, general neurodynia, epilepsy or epilepsy, neurodegenerative disorders, psychiatric disorders is anxiety and depression disease such as, myotony, irregular pulse, dyskinesia, neuroendocrine illness, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, Encelialgia, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, nerve root pain, sciatica, backache, headache or cervicodynia, serious or intractable pain, nociceptive pain, explosive pain, postoperative pain or cancer pain.
Detailed Description Of The Invention
In one aspect, the present invention provides the compound of formula I:
Or its pharmacologically acceptable salt,
Wherein, when occurring it is independently every time:
R1For H, C1-C8 alkyl, C3-C8 cycloalkyl, halogen, CN, NR8SO2R8��SO2R8��SR8��SOR8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3, Heterocyclylalkyl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or two R1It is combined together to form oxo group, or 3 to 7 yuan of fused rings alkyl rings, or the ring of 3 to 7 yuan of volutions;
R2For H, C1-C8 alkyl, halogen, C1-C8 haloalkyl, CN, OH, SO2R8��SR8��SOR8��CO2R8��CON(R8)2��COR8��SO2N(R8)2��CF3��CHF2, or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute;
R3For H, C1-C8 alkyl, C3-C8 cycloalkyl, CO2R8��COR8��COH��CON(R8)2��CF3��CH2CF3��CH2CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute;
R4For H, C1-C8 alkyl, halogen, C3-C8 cycloalkyl, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or 2 R4It is combined together to form 3 to 7 yuan of cycloalkyl rings of thick conjunction;
R8For H, C1-C8 alkyl, CF3, C3-C8 cycloalkyl, fluoro-alkyl, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR replaces, or 2 R8The atom being connected with them is combined together to form ring;
R9For H, CF3��CO2R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, Heterocyclylalkyl, N (R)2��NRCOR��CON(R)2, CN, halogen or SO2R;
R is H, C1-C8 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl or Heterocyclylalkyl;
A is the optional aryl, heteroaryl or the heterocycle that replace;
M is the integer of 0 to 4, comprises end value;
N is the integer of 0 to 3, comprises end value; And
O is the integer of 0 to 4, comprises end value.
In yet another aspect, the present invention provides the compound or pharmaceutically acceptable salt thereof of formula I, when wherein occurring is independently every time:
R1For H, C1-C6 alkyl, C3-C8 cycloalkyl, halogen, CN, NR8SO2R8��SO2R8��SR8��SOR8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3, Heterocyclylalkyl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or two R1It is combined together to form oxo group, or 3 to 7 yuan of fused rings alkyl rings, or the ring of 3 to 7 yuan of volutions;
R2For H, C1-C6 alkyl, C1-C6 haloalkyl, CN, OH, SO2R8��SR8��SOR8��CO2R8��CON(R8)2��SO2N(R8)2��CF3��CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute;
R3For H, C1-C6 alkyl, C3-C8 cycloalkyl, CO2R8��COR8��COH��CON(R8)2��CF3��CH2CF3��CH2CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R4For H, C1-C6 alkyl, halogen, C3-C8 cycloalkyl, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or 2 R4It is combined together to form 3 to 7 yuan of cycloalkyl rings of thick conjunction;
R8For H, C1-C6 alkyl, CF3, C3-C8 cycloalkyl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR substitutes, or 2 R8The atom being connected with them is combined together to form ring;
R9For H, CF3��CO2R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, Heterocyclylalkyl, N (R)2��NRCOR��CON(R)2, CN or SO2R;
R is H, C1-C6 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl or Heterocyclylalkyl;
A is the optional aryl, heteroaryl or the heterocycle that replace;
M is the integer of 0 to 4, comprises end value;
N is the integer of 0 to 3, comprises end value; And
O is the integer of 0 to 4, comprises end value.
For the present invention, according to the periodic table of elements (PeriodicTableoftheElements) the CAS version qualification chemical element of chemistry and physics handbook (HandbookofChemistryandPhysics) the 75th edition. In addition, the General Principle of organic chemistry describes at " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March ' sAdvancedOrganicChemistry ", the 5th edition, editor: Smith, and March, M.B. J., JohnWiley&Sons, in NewYork:2001, its whole content is incorporated to herein as a reference.
As described herein, the compound of the present invention can optionally be replaced by one or more substituting group, that such as above-mentioned generality is set forth or such as the substituting group by the particular category of the present invention, sub-class and kind example. Phrase " optional replace " can use interchangeably with phrase " replacement or do not replace ". As described herein, the variable R in formula I1-R9Contain special groups, such as such as alkyl and aryl. Unless otherwise explanation, otherwise variable R1-R8Special groups can optionally be replaced by one or more following substituting group: halogen, cyano group, oxyalkoxy, hydroxyl, amino, nitro, aryl, haloalkyl and alkyl. Such as, alkyl can optionally be replaced by one or more following radicals: halogen, cyano group, oxyalkoxy, hydroxyl, amino, nitro, aryl, haloalkyl and alkyl. As other example, aromatic yl group can optionally be replaced by one or more following radicals: halogen, cyano group, alkoxyl group, hydroxyl, nitro, haloalkyl and alkyl. Such as those of ordinary skill in the art it will be appreciated that the substituting group envisioned of the present invention be combined as the combination causing and forming stable or chemically feasible compound. Term as used herein " stable " refer to when compound stand to allow its preparation, detection and preferably its reclaim, purifying and the compound for substantially changing during the condition of one or more object disclosed herein. In certain embodiments, stable compound or chemically feasible compound for when moisture or other chemical reactivity condition not in the presence of, the compound that under remaining on the temperature of less than 40 DEG C, at least one week does not change substantially. When two alkoxyl groups are in conjunction with same atom or adjacent atom, two alkoxyl groups can form ring together with the atom that they combine.
Usually, no matter whether term " replacement " have term " optional " before, all refers to specifying the group displacement of substituting group to the hydrogen base in fixed structure. Specified substituent describes in definition above with the description of hereafter compound and the example. Unless otherwise explanation, otherwise the optional group replaced can have substituting group by the position of substitution in each of this group, and when any give fixed structure more than a position can be exceeded one be selected from specify group substituting group replace, substituting group can be identical or different in each position. Ring substituents such as Heterocyclylalkyl can in conjunction with another ring, such as cycloalkyl, and to form spiral shell-bicyclic system, such as two rings share a common atom. Such as those of ordinary skill in the art it will be appreciated that the substituting group envisioned of the present invention be combined as the combination causing and forming stable or chemically feasible compound.
Phrase as used herein " at the most " refer to zero or any integer of numeral after being equal to or less than this phrase. Such as, " at the most 3 " mean any one in 0,1,2 and 3.
Term as used herein " aliphatics ", " fatty group " or " alkyl " refer to straight chain that is completely saturated or that comprise one or more unsaturated unit (that is, without side chain) or side chain, replacement or the hydrocarbon chain that do not replace. Unless otherwise explanation, otherwise fatty group comprises 1-20 aliphatic carbon atom. In certain embodiments, fatty group comprises 1-10 aliphatic carbon atom. In other embodiments, fatty group comprises 1-8 aliphatic carbon atom. In still other embodiment, fatty group comprises 1-6 aliphatic carbon atom, and in still other embodiment, fatty group comprises 1-4 aliphatic carbon atom. Suitable fatty group comprises, but be not limited to straight or branched, replace or do not replace alkyl, alkenyl, alkynes base. Term " cyclic aliphatic " or " cycloalkyl " refer to completely saturated or comprise one or more unsaturated unit but be not aromatic series and the monocyclic hydrocarbon with the singular association point connecting molecule rest part, bicyclic hydrocarbon or tricyclic hydrocarbon. In certain embodiments, " cyclic aliphatic " refer to completely saturated or comprise one or more unsaturated unit but be not aromatic series and the monocycle C with the singular association point connecting molecule rest part3-C8The C of hydrocarbon or two rings8-C12Hydrocarbon, any independent ring of wherein said bicyclic system has 3-7 member.
Term as used herein " electron-withdrawing group " refers to that relative to hydrogen be electronegative atom or group. See, such as " AdvancedOrganicChemistry:Reactions, Mechanisms, andStructure, " JerryMarch, the 4th edition, JohnWiley&Sons (1992), such as, 14-16,18-19 page etc. Exemplary such substituting group comprises halogen, such as Cl, Br or F, CN, COOH, CF3Deng.
Unless otherwise explanation, otherwise term " heterocycle ", " heterocyclic radical ", " heterocyclic aliphatic base ", " Heterocyclylalkyl " or " heterocycle " refer to that one or more annular atomses of wherein one or more ring memberses are independently selected heteroatomic non-aromatic, monocyclic, bicyclic or tricyclic loop systems as used herein. The ring of heterocycle can be saturated, maybe can comprise one or more unsaturated link(age). In certain embodiments; " heterocycle ", " heterocyclic radical ", " heterocyclic aliphatic base ", " Heterocyclylalkyl " or " heterocycle " group there are three to ten four ring memberses; wherein one or more ring memberses are the heteroatoms independently selected from oxygen, sulphur, nitrogen or phosphorus, and in loop systems, each ring comprises 3 to 7 ring memberses.
Term " heteroatoms " refers to that oxygen, sulphur, nitrogen, phosphorus or silicon (comprise, any oxidised form of nitrogen, sulphur, phosphorus or silicon; The season ammonium form of any basic nitrogen, or; The nitrogen replaced of the ring of heterocycle, such as N (as in 3,4-dihydro-2 h-pyrrole base), NH (as in pyrrolidyl) or NR+(as in the pyrrolidyl that replaces at N-)).
Term as used herein " unsaturated " refers to have one or more unsaturated unit but is not aromatic part.
Term as used herein " alkoxyl group " or " alkylthio " refer to be connected to the fatty group as defined before of main carbochain by oxygen (" alkoxyl group ") or sulphur (" alkylthio ") atom. Alkoxyl group as used herein comprises alkenyloxy and alkynyloxy group.
Separately or the term " aryl " of the part use divided as larger portion in " aralkyl ", " aralkoxy " or " aryloxy alkyl " refer to always have the monocycle of five to ten four ring carbon atoms, two rings and three ring loop systems, wherein in this system, at least one ring is aromatic series, and wherein each ring in this system comprises 3 to 7 ring carbon atoms. Term " aryl " can use interchangeably with term " aryl rings ".
Separately or the term " heteroaryl " of the part use divided as larger portion in " heteroaralkyl " or " heteroarylalkoxy " refer to always have the monocycle of five to ten four ring carbon atoms, two rings and three ring loop systems, wherein in this system, at least one ring is aromatic series, at least one ring in this system comprises one or more heteroatoms, and wherein each ring in this system comprises 3 to 7 ring memberses. Term " heteroaryl " can use interchangeably with term " heteroaryl ring " or term " heteroaromatic ".
Term " alkylidene chain " refers to can be completely saturated or have one or more unsaturated unit and have the straight or branched carbochain of two tie points being connected to molecule rest part.
Unless otherwise explanation, otherwise structure described herein also means to comprise all isometrys (such as enantiomerism, diastereo-isomerism and geometry (or conformation)) form of this structure; Such as, R and the S configuration of each asymmetric center, (Z) and (E) double bond isomer, and (Z) and (E) conformer. Therefore, the single three-dimensional chemical isomer of the compounds of this invention and enantiomer, diastereomer and geometry (or conformation) mixture are all within the scope of the present invention.
Unless otherwise explanation, otherwise all tautomerism forms of the compounds of this invention are all within the scope of the present invention. Therefore, the tautomer of the compound of formula I comprises within the scope of the present invention.
In addition, unless otherwise explanation, structure described herein also means to comprise the compound that its difference only is to exist one or more isotopic enrichment atom. Such as, wherein one or more hydrogen atoms are substituted or one or more carbon atom quilt by deuterium or tritium13C-or14The compound of the formula I that the carbon of C-enrichment substitutes is within the scope of the present invention. Such compound is as the probe in such as analysis tool, biological assay or the sodium channel blockers improving treatment characteristic.
In various and accompanying drawing, crosscut ring and be bonded to the line of R group, such as in following formula,
Mean that, when valency allows, this R group can be bonded any carbon of this ring, or (if suitable) heteroatoms such as N.
At such as such as R1��R2��R3��R4��R5, R6Or R7Term definition within, work as CH2The MU (methylene unit) that unit maybe can exchange can by O, CO, S, SO, SO2Or NR8During replacement, it means to comprise any CH2Unit, the CH being included in terminal methyl group2. Such as ,-CH2CH2CH2SH within the definition of C1-C8 alkyl, wherein two CH at the most2Unit can be substituted by S, because the CH of non-terminal methyl2Unit is substituted by S.
In another embodiment, the present invention characterizes the compound of formula I and appended definition, wherein R1For C1-C8 alkyl or two R1The atom being connected with them is combined together to form the cycloalkyl of 3 to 7 yuan of thick conjunctions or the ring of volution. In another embodiment, R1For CH3Or two R1It is combined together to form the cyclohexyl ring of thick conjunction.
In another embodiment, the present invention characterizes the compound of formula I and appended definition, wherein R2For H, C1-C8 alkyl, halogen, CF3��CN��CON(R8)2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute. In another embodiment, R2For COCF3��COtBu��Cl��COCH3��CF2CF3��CH2CF3��CF3��CN��Br��COCH(CH3)2��COCH2CH3��CH(OH)CF3��SO2CH3��COPh��Or
In another embodiment, the present invention characterizes the compound of formula I and appended definition, wherein R3For H, C1-C8 alkyl, CO2R8��COR8��COH��CON(R8)2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, CF2��S��SO��SO2Or NR8Substitute. In another embodiment, R3For H, CH3��CH2CH3��CH2CH2OCH3, benzyl, CH2CH(CH2)2��CH(CH2)2, cyclobutyl, COCH3��CO2CH3��CO2CH2CH3��CH2CF3��CH2CHF2��COH��CON(CH3)2Or CONHCH3��
In another embodiment, the present invention characterizes the compound of formula I and appended definition, wherein R4For H, halogen or C1-C8 alkyl. In another embodiment, R4For H, F or CH3��
In another embodiment, the present invention characterizes the compound of formula I and appended definition, and wherein m is 0,1 or 2. In another embodiment, n is 0,1 or 2. In another embodiment, O is 0 or 1.
In another embodiment, the present invention characterizes the compound of formula I and appended definition, and wherein A is
Wherein:
R5For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CHF2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R6For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, C3-C8 ring alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R7For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��OSO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-(R9)p, wherein p is 1 or 2 and wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute; Or
R5With R6, or R6With R7It is all C1-C8 alkyl when occurring for twice, and forms, together with the carbon connected with them, the ring comprising 2 heteroatomic optional replacements at the most.
In another embodiment, the present invention characterizes the compound of formula I and appended definition, wherein R5For H, C1-C8 alkyl, C1-C8 alkoxyl group, halogen, OCF3��OCHF2��R9Or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR7Substitute. In another embodiment, R5For H, CH3��OCH3��OCF3��OPh��Ph��OCHF2Or F.
In another embodiment, the present invention characterizes the compound of formula I and appended definition, wherein R6For H, C1-C8 alkyl, C1-C8 alkoxyl group, halogen, R9, or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute. In another embodiment, R6For H, CH3��OCH3��OCH2CH3��OCH2CH2CH3��OCH(CH3)2��CF3��CN��Ph��SO2CH3��OH��CH(CH3)2��OCH2CH2CH2CH3, F, Cl or CH2OH��
In another embodiment, the present invention characterizes the compound of formula I and appended definition, wherein R7For H, C1-C8 alkyl, C1-C8 alkoxyl group, SO2R8��OSO2R8��SO2N(R8)2��R9, or straight chain, side chain or ring-type (C1-C8)-(R9)p, wherein p is 1 or 2 and wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute. In another embodiment, R7For H, CH2CH3, tBu, Cl, F, OH, C (=CH2)CH3, OC (=CH2)CH3��OCH3��OCH2CH2CH2CH3��CH2OH��OCH2CH2OH��OCH2CH2CH2OH��OtBu��OCH(CH3)(CH2CH3)��OCH2C(CH3)2OH��C(CH3)2OH��CH2C(CH3)2OH��CH(OH)CH(CH3)2��C(CH3)2CH2OH��OCH2CH2CH(CH3)2��OCH2CH2CH3��OCH(CH3)2��OCH2CH2OCH3��SO2CH3��SO2tBu��SO2CH2CH3��SO2CH2CH(CH3)2��SO2CH(CH3)2��SO2NH(CH3)��SO2NH(CH(CH2)2)��SO2NH(CH2CH3)��SO2NH(CH(CH3)2)��SO2N(CH3)2��Ph��OCH2CH2OCH3��CH(CH3)2��SO2N(CH2CH3)2��CH2CH2CH2CH3��CH2CH2CH3��OPh��OCH2CH2CH2CH3��CH2OPh��OCH2Ph��CH2CH2CH2CH2CH3��OCH2CH3��OCH2CH(CH3)2��CH2CH3��CH2Ph��CCCH2OCH3��SO2CHF2��OCF3��OCHF2��CH2CH(CH3)2��OCH2tBu��OCH2CF3��CH2OCH2CH2CF3��CH2OCH2CF3��SO2CF3��C(CH3)2CH2CH3��C(CH2CH3)3��CH(OCH2CF3)2��CF3��OCH2C(CH3)2F�� CH(OH)CH2OCH2CF3��CH(OCH2CF3)CH2OH��OSO2CF3��Or OCH2CH2OCF3��
In another embodiment, the present invention characterizes the compound of formula I and appended definition, and wherein A isAnd be selected from:
In another embodiment, the present invention characterizes the compound of formula I and appended definition, and wherein A is heteroaryl or heterocycle. In another embodiment, A comprises 1 to 3 heteroatomic bicyclic heteroaryl independently selected from N, O or S. In another embodiment, A is selected from and comprises 1 to 3 heteroatomic bicyclic heteroaryl independently selected from N, O or S.
In another embodiment, the present invention characterizes the compound of formula I and appended definition, and wherein A is selected from following radicals:
In another embodiment, the compound of the present invention has formula IA:
Wherein:
R2For H, C1-C8 alkyl, halogen, C1-C8 haloalkyl, CN, OH, SO2R8��SR8��SOR8��COR8��CO2R8��CON(R8)2��SO2N(R8)2��CF3��CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute;
R3For H, C1-C8 alkyl, CO2R8��COR8��COH��CON(R8)2��CF3Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, CF2��S��SO��SO2Or NR8Substitute;
R6For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, C3-C8 ring alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R7For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute.
In another embodiment, the present invention characterizes the compound of formula IA and appended definition, wherein R2For H, COCF3��COtBu��Cl��COCH3��CF2CF3��CH2CF3��CF3��CN��Br��COCH(CH3)2��COCH2CH3��CH(OH)CF3��SO2CH3��COPh��Or
In another embodiment, the present invention characterizes the compound of formula IA and appended definition, wherein R3For H, CH3��CH2CH3��CH2CH2OCH3��CH2CH2OH��CH2CO2CH2CH3��CH2CON(CH3)2��CH2CONH2��CH2CN, benzyl, cyclobutyl, CH2CH(CH2)2��CH(CH2)2��CH2CF3��CH2CHF2��COCH3��COCH2CH3��CO2CH3��CO2CH2CH3��COH��CONH(CH3)2Or CONHCH3��
In another embodiment, the present invention characterizes the compound of formula IA and appended definition, wherein R6For H, CH3��OCH3��OCH2CH3��OCH2CH2CH3��OCH(CH3)2��CF3��CN��Ph��SO2CH3��OH��CH(CH3)2��OCH2CH2CH2CH3, F, Cl or CH2OH��
In another embodiment, the present invention characterizes the compound of formula IA and appended definition, wherein R7For H, CH3��CH2CH3��tBu��Cl��F��OH��C(=CH2)CH3��OC(=CH2)CH3��OCH3��OCH2CH2CH2CH3��CH2OH��OCH2CH2OH��OCH2CH2CH2OH��OtBu��OCH(CH3)(CH2CH3)��OCH2C(CH3)2OH��C(CH3)2OH��CH2C(CH3)2OH��CH(OH)CH(CH3)2��C(CH3)2CH2OH��OCH2CH2CH(CH3)2��OCH2CH2CH3��OCH(CH3)2��OCH2CH2OCH3��SO2CH3��SO2tBu��SO2CH2CH3��SO2CH2CH(CH3)2��SO2CH(CH3)2��SO2NH(CH3)��SO2NH(CH(CH2)2)��SO2NH(CH2CH3)��SO2NH(CH(CH3)2)��SO2N(CH3)2��OPh��Ph��OCH2CH2OCH3��CH(CH3)2��SO2N(CH2CH2CH3)2��CH2CH2CH2CH3��CH2CH2CH3��OCH2CH2CH2CH3��CH2OPh��OCH2Ph��CH2CH2CH2CH2CH3��OCH2CH3��OCH2CH(CH3)2��CH2Ph��CCCH2OCH3��SO2CHF2��OCF3��OCHF2��CH2CH(CH3)2��OCH2tBu��OCH2CF3�� CH2OCH2CH2CF3��CH2OCH2CF3��SO2CF3��C(CH3)2CH2CH3��C(CH2CH3)3��CH(OCH2CF3)2��CF3��OCH2C(CH3)2F�� CH(OH)CH2OCH2CF3��CH(OCH2CF3)CH2OH��OSO2CF3��Or OCH2CH2OCF3��
In another embodiment, the present invention characterizes the compound of formula IA and appended definition, wherein R2For H, CF3��COCF3��COtBu��Cl��COCH3��CF2CF3��CH2CF3Or CN; R3For H, CH2CH2OCH3, benzyl, CH3��CH2CH3��CH2CH(CH2)2, cyclobutyl, COCH3��CO2CH3��COH��CH(CH2)2��CH2CF3��CH2CHF2��CO2CH2CH3��CON(CH3)2Or CONHCH3; R6For CH3��OCH3��OCH2CH3��OCH2CH2CH2CH3��CH2OH, F or Cl; And R7For F, CH2CH3��tBu��OH��OCH3��OCH2CH2CH2CH3��OtBu��OCH(CH3)(CH2CH3)��OCH2CH2OH��OCH2CH2CH2OH��OCH2C(CH3)2OH��C(CH3)2OH��C(=CH2)CH3��OC(=CH2)CH3��CH2OH��C(CH3)2CH2OH��OCH2CH2CH(CH3)2��OCH2CH2CH3��OCH(CH3)2��OCH2CH2OCH3��SO2CH3��SO2CH2CH3��SO2CH(CH3)2��SO2NH(CH3)��SO2NH(CH(CH2)2)��SO2NH(CH2CH3)��SO2NH(CH(CH3)2)��SO2N(CH3)2Or OCH2CH2OCF3��
In another embodiment, the present invention characterizes the compound of formula IA and appended definition, whereinPart is selected from:
In another embodiment, the present invention characterizes the compound of formula I, and wherein said compound is selected from table 1:
In yet another aspect, the present invention characterizes and comprises the compound of the present invention and the pharmaceutical composition of pharmaceutically acceptable carrier.
In yet another aspect, the present invention characterize a kind of suppress following in the method for Voltage-gated sodium channels:
Patient; Or
Biological sample;
It comprises compound from the present invention to patient or the composition of using, or makes this biological sample contact compound or the composition of the present invention. In another embodiment, described Voltage-gated sodium channels is NaV1.7.
In yet another aspect, the present invention characterizes following disease in a kind of experimenter for the treatment of or alleviates the method for its severity: acute, chronic, nervosa or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, general neurodynia, epilepsy or epilepsy, neurodegenerative illness, psychiatric disorders, anxiety, dysthymia disorders, bipolar disorders (dipolardisorder), myotony, irregular pulse, dyskinesia, neuroendocrine illness, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, Encelialgia, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, nerve root pain, sciatica, backache, headache or cervicodynia, serious or intractable pain, nociceptive pain, explosive pain, postoperative pain, cancer pain, apoplexy, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, the angina of pressure or exercise induced, palpitaition, hypertension, migraine or abnormal gastrointestinal are wriggled, and it comprises compound or the composition of the present invention using significant quantity.
In another embodiment, described method is used for the treatment of following disease or alleviates its severity: femur pain caused by cancer; Non-malignant chronic ostalgia; Rheumatoid arthritis; Osteoarthritis; Spinal canal stenosis; Nervosa low back pain; Nervosa low back pain; Myofascial pain syndrome; Fibromyalgia; Temporomandibular joint (TMJ) pain; Chronic visceral pain, stomachache; Pancreas; IBS pain; Chronic and acute headache; Migraine; Tension headache, comprises cluster headache; Chronic and acute neuropathic pain, postherpetic neuralgia; Diabetic neuropathy becomes; HIV-associated neurological disease; Trigeminal neuralgia; Charcot-MarieTooth neuropathy; Heredity esthesioneurosis; Peripheral nerve injury; Pain neuroma; The nearly side of dystopy and distally electric discharge (ectopicproximalanddistaldischarges); Radiculopathy; The neuropathic pain of chemotherapy induction; The neuropathic pain that radiotherapy is brought out; Post mastectomy pain; Central pain; Spinal cord injury pain; Post-stroke pain; Thalamic pain; Complicacy regional pain syndrome; Phantom limb pain; Intractable pain; Acute pain, acute postoperative pain; Acute flesh skeleton pain; Arthrodynia; Mechanicalness low back pain; Cervicodynia; Tendonitis; Damage/motion pain; Acute Encelialgia, stomachache; Pyelonephritis; Ecphyaditis; Cholecystitis; Intestinal obstruction; Hernia; Pectoralgia; Pained; Pelvis pain, renal colic; Acute labor pains, product pain; Cesarean section pain; Acute inflammation; Burn and trauma pain; Acute intermittent pain, endometriosis; Acute herpes zoster pain; Sicklemia; Acute pancreatitis; Explosive pain; Mouth face ache, comprises sinusitis paranasal sinusitis pain, toothache; Multiple sclerosis (MS) pain; Dysthymia disorders pain; Leprosy pain; Behcets disease pain; Adiposis dolorosa; Phlebitis pain; Guillain-Barre pain; Thigh and movable toe pain caused (painfullegsandmovingtoes); Haglund syndrome; Erythromelalgia; Method cloth Richter scale disease pain; Bladder and urogenital disease, comprise the urinary incontinence; Bladder hyperactivity; Painful bladder syndrome; Interstitial cystitis (IC); Prostatitis; Complicacy regional pain syndrome (CRPS), I type and II type; Popularity pain, paroxysmal severe pain disease, pruritus, tinnitus or angina bringing out property pain.
The compound of the present invention can easily use following method to prepare. Following proposal 1 to scheme 4 has been set forth the method for the compound of preparation the present invention.
Scheme 1
X=leavings group or NH2; R3=alkyl.
a)H+: protonic acid, such as acetic acid or tosic acid, NaOAc; B) H2NR3, solvent is (such as: EtOH or CH3CN)��
Scheme 2
PG1The protecting group (such as: Boc) that=acid is unstable; PG2Such as: cbz, the protecting group (phenmethyl) that=acid is stable; R3=alkyl.
a)PG1=Boc; Boc2O, alkali is (such as: Et3N), solvent (such as: THF); B) PG2=cbz; 2,5-dioxo tetramethyleneimine-1-base methyl phenyl carbonate, alkali is (such as: Et3N), solvent (such as: THF); C) PG1=Boc; H+(such as: HCl or TFA), solvent is (such as: iPrOH, EtOH, CH3CN or CH2Cl2); D) H+: protonic acid, such as acetic acid or tosic acid, NaOAc; E) R3-X, alkali is (such as: NaH or K2CO3), solvent is (such as: DMF, THF or CH3CN); F) PG2=cbz; Pd/C, H2, solvent is (such as: iPrOH, EtOH or CH3CN)��
Scheme 3
PG=protecting group, such as Boc, phenmethyl, cbz; R3=H or alkyl.
A) catalysis H+: protonic acid is trifluoroacetic acid, tosic acid or dichloro acetic acid such as, solvent (such as: EtOH); B) R5=CF3, 5-(trifluoromethyl)-5H-dibenzo [b, d] thiophene (thiophenium) trifluoromethayl sulfonic acid ester, alkali is (such as: K2CO3), solvent is (such as: CH3Or R CN)5=alkylhalide group; Alkylhalide group iodide are (such as: CF3I��CF3CH2I or CF3CF2I)��FeSO4��6H2O��H2O2, solvent (such as: DMSO); R5=CN, chlorosulfonic acid isocyanate, solvent (such as: THF or DMF); R5=Cl��CF3SO2Cl, solvent are (such as: CH2Cl2); R5=R6C (O), acylating agent are (such as: R6C(O)2O��R6C (O) Cl), alkali is (such as: pyridine, Et3N or DBN), solvent (such as: CH2Cl2, DCE or THF) or i) NBS, CH2Cl2; Ii) CH3(CH2)nOCH=CHR7, catalyzer is (such as: Pd2dba3��CHCl3), solvent (such as: two alkane); C) PG=Boc, H+(such as: HCl or TFA), solvent are (such as: iPrOH, EtOH, CH3CN or CH2Cl2); PG=cbz; Pd/C, H2, solvent (such as: iPrOH, EtOH or CH3CN); D) A CO2H; Coupling agent (such as: HATU or EDCI), alkali is (such as: Et3N or iPr2NEt), solvent is (such as: DMF, CH3CN or CH2Cl2); Or A C (O)-Cl, NaOH, solvent (such as: water and MTBE).
Scheme 4
R3=acyl group; R6=PG or C (O) A; R7=alkyl.
a)R3-X (X=leavings group, such as: halogen, OTs), alkali are (such as: K2CO3��Et3N or pyridine), solvent (such as: DMF, THF, ACN, CH2Cl2Or pyridine); B) R8=H; R7-NCO, alkali are (such as: Et3N), solvent (such as: THF) or ClC (O) NR7R8, alkali (such as: pyridine).
Purposes, preparation and administration
Can medicinal compositions
As discussed above, the present invention is provided as the compound of Voltage-gated sodium channels inhibitor, and the compound of therefore the present invention is used for the treatment of and comprises, but it is not limited to following disease, disorder and illness: acute, chronic, nervosa or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, general neurodynia, epilepsy or epilepsy, neurodegenerative illness, psychiatric disorders is anxiety and depression disease such as, myotony, irregular pulse, dyskinesia, neuroendocrine illness, ataxia, multiple sclerosis, irritable bowel syndrome and incontinence. therefore, in another aspect of the present invention, it is provided that can medicinal compositions, wherein these compositions comprise any one of compound as described herein, and optionally comprise pharmaceutically acceptable carrier, auxiliary material or vehicle. in certain embodiments, these compositions optionally comprise one or more other therapeutical agents further.
It is also understood that the compound of some the present invention can exist for the free form for the treatment of, or when appropriate, can medicinal derivative form exist in it. According to the present invention, can comprise by medicinal derivative, but being not limited to pharmacologically acceptable salt, ester, the salt of such ester or other adducts any or derivative, it is to can directly or indirectly provide the compound as described in addition or its metabolite or resistates during the snibject needed herein.
Term as used herein " pharmacologically acceptable salt " refers to those salt in reasonable medical judgment (soundmedicaljudgment) scope, it is applicable to contact the tissue of people and lower animal, and there is no undue toxicity, stimulation, transformation reactions etc., and there is rational interests/risk ratio. " pharmacologically acceptable salt " refers to any nontoxic salt of the compound of the present invention or the salt of its ester, and it is when being administered to recipient, it is possible to directly or indirectly provide compound or its inhibit activities metabolite or the resistates of the present invention. Term as used herein " inhibit activities metabolite or its resistates " refers to that its metabolite or resistates are also the inhibitor of Voltage-gated sodium channels.
Pharmacologically acceptable salt is well known in the art. such as, S.M.Berge, waits people at J.PharmaceuticalSciences, describes pharmacologically acceptable salt in detail, be incorporated to herein as a reference in 1977,66,1 19. the pharmacologically acceptable salt of the compound of the present invention comprises derived from those of suitable mineral acid and organic acid and mineral alkali and organic bases. can example medicinal, non-toxic acid salt be with mineral acid than example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid or with organic acid such as acetic acid, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid, or with the use of this area use other method such as ion-exchange formed amide. other pharmacologically acceptable salt comprises adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, dextrocamphoric acid salt, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodide, 2-hydroxy-ethanesulfonic acid salt, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, embonate (pamoate), pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, p-tosylate, undeeanoic acid salt, valerate etc. salt derived from suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt. The present invention it is also contemplated that compound disclosed herein any alkalescence nitrogen-containing group season ammonium. Water-soluble or oil soluble or water-dispersible or oil dispersibility product can be obtained by such season ammoniumization. Representative basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc. Other pharmacologically acceptable salt comprise (when appropriate) nontoxicity ammonium, season ammonium and use counter ion formed amine positively charged ion, described counter ion are halogen ion, hydroxide radical, carboxylate radical, sulfate radical, phosphate radical, nitrate radical, low alkyl group sulfonate radical and aryl sulfonic acid root such as.
As mentioned above, the present invention can comprise pharmaceutically acceptable carrier, auxiliary material or vehicle by medicinal compositions in addition, its comprise as used herein any and all solvents, thinner or other liquid vehicle, dispersion aids or suspending agent, tensio-active agent, etc. penetration enhancer, thickening material or emulsifying agent, sanitas, solid binder, lubricant etc., it is applicable to required particular dosage form. Remington ' sPharmaceuticalSciences, the 16 edition, E.W.Martin (MackPublishingCo., Easton, Pa., 1980) discloses can the various carrier of medicinal compositions and the known technology of preparation thereof for preparing. unless any conventional mounting medium is incompatible with the compound of the present invention, such as produce any undesirably biological action or other with harmful way with can other component interaction any of medicinal compositions, otherwise desired use is within the scope of the present invention. some examples of the material that can serve as pharmaceutically acceptable carrier comprise, but it is not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein is human serum albumin such as, buffer substance is phosphoric acid salt such as, glycine, Sorbic Acid or potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolytic condenser are such as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silica, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylic ester, wax, polyethylene-polyoxypropylene-block polymer, lanolin, sugar is lactose such as, dextrose plus saccharose, starch such as W-Gum and yam starch, cellulose and its derivates, such as Xylo-Mucine, ethyl cellulose and rhodia, powder tragakanta, Fructus Hordei Germinatus, gelatin, talcum powder, vehicle such as theobroma oil and suppository wax, oil, such as peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil, glycol, such as propylene glycol or polyoxyethylene glycol, ester, such as ethyl oleate and Laurate ethyl, agar, buffer reagent, such as magnesium hydroxide and aluminium hydroxide, Lalgine, the water of pyrogen-free, isotonic saline solution, Ringer's solution, ethanol and phosphate buffered saline buffer, and other non-toxic compatible lubricant, such as sodium lauryl sulphate and Magnesium Stearate, and tinting material, releasing agent, coating-forming agent, sweeting agent, seasonings and perfume compound, judgement according to allotment teacher, sanitas and oxidation inhibitor can also be present in composition.
Compound and can the purposes of medicinal compositions
In yet another aspect, there is provided a kind of to treat following disease or alleviate the method for its severity: acute, chronic, nervosa or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, general neurodynia, epilepsy or epilepsy, neural change neurodegenerative disorder, psychiatric disorders is anxiety and depression disease such as, bipolar disorders, myotony, irregular pulse, dyskinesia, neuroendocrine illness, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, Encelialgia, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy becomes, nerve root pain, sciatica, backache, headache or cervicodynia, serious or intractable pain, nociceptive pain, explosive pain, postoperative pain, or cancer pain, it comprise to its experimenter of needs use the compound of significant quantity or comprise compound can medicinal compositions.
In certain embodiments, there is provided a kind of to treat following disease or alleviate the method for its severity: the angina of apoplexy, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, pressure or exercise induced, palpitaition, hypertension, migraine or abnormal gastrointestinal are wriggled, it comprise to its experimenter of needs use the compound of significant quantity or comprise compound can medicinal compositions.
In certain embodiments, it is provided that a kind of be used for the treatment of acute, chronic, nervosa or inflammatory pain or alleviate the method for its severity, it comprise to its experimenter of needs use significant quantity compound or can medicinal compositions. In some other embodiment, it is provided that a kind of method being used for the treatment of nerve root pain, sciatica, backache, headache or cervicodynia, it comprise to its experimenter of needs use significant quantity compound or can medicinal compositions. In still other embodiment, there is provided a kind of to be used for the treatment of serious or intractable pain, acute pain, postoperative pain, backache, tinnitus or cancer pain or alleviate the method for its severity, it comprise to its experimenter of needs use significant quantity compound or can medicinal compositions.
In certain embodiments, a kind of it be used for the treatment of following disease or alleviate the method for its severity: femur pain caused by cancer; Non-malignant chronic ostalgia; Rheumatoid arthritis; Osteoarthritis; Spinal canal stenosis; Nervosa low back pain; Nervosa low back pain; Myofascial pain syndrome; Fibromyalgia; Temporomandibular joint (TMJ) pain; Chronic visceral pain, comprises stomachache; Pancreas; IBS pain; Chronic and acute headache; Migraine; Tension headache, comprises cluster headache; Chronic and acute neuropathic pain, comprises postherpetic neuralgia; Diabetic neuropathy becomes; HIV-associated neurological disease; Trigeminal neuralgia; Charcot-MarieTooth neuropathy; Heredity esthesioneurosis; Peripheral nerve injury; Pain neuroma; The nearly side of dystopy and distally electric discharge (ectopicproximalanddistaldischarges); Radiculopathy; The neuropathic pain of chemotherapy induction; The neuropathic pain that radiotherapy is brought out; Post mastectomy pain; Central pain; Spinal cord injury pain; Post-stroke pain; Thalamic pain; Complicacy regional pain syndrome; Phantom limb pain; Intractable pain; Acute pain, acute postoperative pain; Acute flesh skeleton pain; Arthrodynia; Mechanicalness low back pain; Cervicodynia; Tendonitis; Damage/motion pain; Acute Encelialgia, comprises stomachache; Pyelonephritis; Ecphyaditis; Cholecystitis; Intestinal obstruction; Hernia; Deng; Pectoralgia, comprises pained; Pelvis pain, renal colic; Acute labor pains, comprises and produces pain; Cesarean section pain; Acute inflammation; Burn and trauma pain; Acute intermittent pain, comprises endometriosis; Acute herpes zoster pain; Sicklemia; Acute pancreatitis; Explosive pain; Mouth face ache, comprises sinusitis paranasal sinusitis pain, toothache; Multiple sclerosis (MS) pain; Dysthymia disorders pain; Leprosy pain; Behcets disease pain; Adiposis dolorosa; Phlebitis pain; Guillain-Barre pain; Thigh and movable toe pain caused (painfullegsandmovingtoes); Haglund syndrome; Erythromelalgia; Method cloth Richter scale disease pain; Bladder and urogenital disease, comprise the urinary incontinence; Bladder hyperactivity; Painful bladder syndrome; Interstitial cystitis (IC); Prostatitis; Complicacy regional pain syndrome (CRPS), I type and II type; The pain that angina is brought out, it comprise to its experimenter of needs use significant quantity compound or can medicinal compositions.
In certain embodiments of the invention, compound or can " significant quantity " of medicinal compositions be effectively treat in following disease one or more or alleviate the amount of its severity: acute, chronic, nervosa or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, general neurodynia, epilepsy or epilepsy, neurodegenerative illness, psychiatric disorders is anxiety and depression disease such as, myotony, irregular pulse, dyskinesia, neuroendocrine illness, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, Encelialgia, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy becomes, nerve root pain, sciatica, backache, headache or cervicodynia, serious or intractable pain, nociceptive pain, explosive pain, postoperative pain, tinnitus or cancer pain.
Method according to the present invention, compound and composition can use any amount effectively treated in following disease one or more or alleviate its severity and any route of administration to carry out administration: acute, chronic, nervosa or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, general neurodynia, epilepsy or epilepsy, neurodegenerative illness, psychiatric disorders is anxiety and depression disease such as, myotony, irregular pulse, dyskinesia, neuroendocrine illness, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, Encelialgia, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy becomes, nerve root pain, sciatica, backache, headache or cervicodynia, serious or intractable pain, nociceptive pain, explosive pain, postoperative pain, tinnitus or cancer pain. the precise volume needed will be different and change with experimenter, depend on the kind of experimenter, age and general situation, the seriousness of infection, the particular agent of use, its administering mode etc. the compound of the present invention is preferably mixed with and is easy to administration and the uniform dosage unit form of dosage. statement " dosage unit form " refers to be suitable for the physical dispersion unit of the reagent of experimenter to be treated as used herein. however, it is to be understood that total every daily dosage portion of the compound of the present invention and composition should be determined in rational medical judgment category by attending doctor. concrete effective dose level for any particular subject or organism will depend on various factors, comprise illness to be treated and the severity of illness, the activity of the concrete promoting agent used, the concrete composition used, the age of experimenter, body weight, generally healthy state, sex and diet, the administration time of the concrete promoting agent used, route of administration and discharge rate, the time length for the treatment of, with the particular compound combination used or the medicine used simultaneously, and the other factors known in medical field. term as used herein " experimenter " or " patient " refer to animal, it is preferable that Mammals, and the most preferably mankind.
The present invention can medicinal compositions can by oral, rectum, parenteral, brain pond, intravaginal, intraperitoneal, locally (as passed through pulvis, ointment or drops), through cheek or as oral or nasal mist etc. to the mankind and other animals administer, this depends on the severity of sufferer to be treated. In certain embodiments, the compound of the present invention can be about every day 0.01mg/kg to about 50mg/kg and preferably about 1mg/kg to the dosage level oral administration of about 25mg/kg experimenter's body weight/day or parenteral admin, once a day or repeatedly, to obtain the result for the treatment of of expectation.
Liquid dosage form for oral administration includes but not limited to pharmaceutical acceptable emulsion, micro-breast, solution, suspension, syrup and elixir. Except active compound, this liquid dosage form can also comprise the conventional inert diluent in this area, such as water or other solvent, solubilizing agent and emulsifying agent, such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1, particularly, 3-butyleneglycol, dimethyl formamide, oil (Oleum Gossypii semen, peanut oil, Semen Maydis oil, embryo oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and sorbitan fatty acid esters and mixture thereof. Except inert diluent, this oral compositions can also comprise auxiliary material, such as wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and perfume compound.
Can according to known technology, it may also be useful to applicable dispersion agent or wetting agent and suspending agent preparation injectable formulation, such as sterile water for injection or oil-based suspension. Aseptic injection preparation can also be the aseptic injectable solution in the acceptable thinner of parenteral or solvent of nontoxicity, suspension or emulsion, the such as solution in 1,3 butylene glycol. The acceptable carrier that can use or solvent are water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution. In addition, aseptic fixed oil is generally also used as solvent or suspending medium. Object for this reason, it is possible to use the fixed oil of any gentleness, comprises monoglyceride or the triglyceride of synthesis. In addition, fatty acids such as oleic acid may be used in injection formulations.
Injection formulations can be filtered by such as bacterial-retaining strainer or carry out sterilizing by mixing the disinfectant of aseptic solid composite form, and wherein said aseptic solid composite can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
In order to extend the effect of the compounds of this invention, often need to slow down the absorption of the compound from subcutaneous or intramuscularly. This can realize with the use of the liquid suspension of the crystal of poorly water-soluble or amorphous substance. So, the absorption rate of compound will depend on its dissolution rate, and dissolution rate may depend on again crystallographic dimension and crystallized form. Alternately, the absorption of compound form postponing parenteral admin is by realizing this compound dissolution or be suspended in oiliness carrier. The depot formulation of injectable is prepared by forming the microencapsule matrices of compound in Biodegradable polymeric (such as polylactide-PGA). Ratio according to compound and polymkeric substance and the character of concrete polymkeric substance used, it is possible to the rate of release of control compound. The example of other Biodegradable polymeric comprises poly-(ortho ester) and poly-(acid anhydrides). Injectable depot formulation can also be prepared by compound is embedded in the liposome compatible with body tissue or micro-Ruzhong.
The composition of rectum or vagina administration is suppository preferably, it can by mixing by the compound of the present invention prepare with the non-irritating excipient being applicable to or carrier (such as theobroma oil, polyoxyethylene glycol or suppository wax), wherein said vehicle or carrier are solid at ambient temperature, but it is liquid under body temperature, therefore melts in rectum or vaginal canal and discharge active compound.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granule. in these solid dosages, active compound and at least one inertia, pharmaceutically acceptable vehicle or carrier mixing, described vehicle or carrier are such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, and/or a) weighting agent or extender, such as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent, such as, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) wetting Agent for Printing Inks, such as glycerine, d) disintegrating agent, such as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent is dissolved, such as paraffin, f) absorption enhancer, such as quaternary ammonium compounds, g) wetting agent, such as hexadecanol and glyceryl monostearate, h) absorption agent, such as kaolin and wilkinite, and i) lubricant, such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, and their mixture. when capsule, tablet and pill, this formulation can also comprise buffer reagent.
The solids composition of similar type can also be used as weighting agent in soft hard fillibility gelatine capsule, and capsule uses such as lactose or the vehicle such as toffee and macromolecule polyethylene glycol. The solid dosage of tablet, lozenge, capsule, pill and granule can be prepared with dressing and shell such as enteric coating and field of pharmaceutical preparations other coating material known. They optionally can comprise opalizer, it is also possible to is so a kind of composition: they only or preferably discharge one or more activeconstituentss in certain part (optionally with delayed mode) of enteron aisle. The example of the embedding composition that can use comprises polymeric material and wax. The solids composition of similar type can also be used as weighting agent in soft hard fillibility gelatine capsule, and capsule used excipient is such as lactose or toffee, and high molecular weight polyethylene glycol etc.
Active compound can also be present in the microencapsulation formulation with one or more above-mentioned vehicle. The solid dosages such as tablet, lozenge, capsule, pill and particle can be prepared with dressing and shell (such as enteric coating, controlled release coat and pharmaceutical-formulating art other coating material known). In these solid dosages, active compound can mix with at least one inert diluent (such as sucrose, lactose or starch). These formulations can also such as, as practice, comprise other material besides inert diluents, such as tableting lubricant and other compression aids, such as Magnesium Stearate and Microcrystalline Cellulose. When capsule, tablet and pill, this formulation can also comprise buffer reagent. They optionally can comprise opalizer, it is also possible to is so a kind of composition: they only or preferably optionally discharge one or more activeconstituentss with delayed mode in certain part of enteron aisle. The example of the embedding composition that can use comprises polymkeric substance and wax.
The local of the compounds of this invention or the formulation of percutaneous dosing comprise ointment, paste, emulsifiable paste, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch. The buffer reagent that active ingredient aseptically maybe may need with the sanitas of pharmaceutically acceptable carrier and any needs mixes. Ophthalmic preparation, ear drop and eye drops are also contained within the scope of the invention. In addition, the use of transdermal patch is contained in the present invention, and their attendant advantages is controllably to send compound to body. This kind of formulation can by preparing compound dissolution or be scattered in applicable medium. Absorption enhancer can also be used to increase the percutaneous flow of compound. Can by providing rate controlling membranes or carry out speed control by being scattered in polymeric matrix or gel by compound.
As above roughly as described in, the compound of the present invention be suitable for makes Voltage-gated sodium channels inhibitor. in one embodiment, the compound of the present invention and composition are NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, inhibitor one or more in NaV1.8 or NaV1.9, and therefore, do not wish to be bound by any particular theory, this compound and composition are used for the treatment of following disease especially, illness or disorderly or alleviate its severity: wherein NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, activation one or more in NaV1.8 or NaV1.9 or superfunction and disease, illness or disorderly relevant. when the activation of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9 or superfunction and specified disease, illness or disorderly relevant time, this disease, illness or disorder also can be called " disease, illness or disorder that NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9-mediate ". therefore, in yet another aspect, the present invention provides a kind of and treats following disease, illness or disorderly or alleviate the method for its severity: wherein one or more in NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9 activation or superfunction are relevant with disease condition.
Be used as in the present invention the inhibitor of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9 compound activity can according to the method described general in embodiment hereof, or according to those of ordinary skill in the art can method measure.
In the embodiment that some is exemplary, the compound of the present invention is used as the inhibitor of NaV1.7 and/or NaV1.8.
It is further understood that the compound of the present invention and can may be used in combination treatment by medicinal compositions, namely this compound and can the therapeutical agent that can expect with one or more other of medicinal compositions or medical procedures simultaneously, before it or administration after which. Combination for the specific therapy (therapeutical agent or program) of assembled scheme should be considered the consistency of required therapeutical agent and/or program and expect the result for the treatment of of realization. It should also be understood that, same disease can be obtained desired result (such as by therapy used, the compound of the present invention can with other medicament administration simultaneously being used for the treatment of identical illness), such as, or it can obtain different-effect (controlling any side effect). As used herein, it is generally used for treating or prevention specified disease or the other therapeutical agent of illness are called " being suitable for the disease treated or illness ". Such as, exemplary other therapeutical agent includes but not limited to: non-opium pain killer (indoles, such as R-ETODOLAC, indomethacin, sulindac, tolmetin; Naphthyl alkane ketone, such as nabumetone; Former times health, such as piroxicam; P-aminophenyl amphyl, such as Paracetamol; Propionic acid, such as fenoprofen, flurbiprofen, Ibuprofen BP/EP, Ketoprofen, Naproxen Base, naproxen sodium, Taisho); Salicylate, such as Asprin, choline magnesium trisalicylate, diflunisal; That acid class fragrant, such as meclofenamic acid, mefenamic acid; And pyrazoles, such as Phenylbutazone); Or opiates (narcotic) agonist (such as morphine monomethyl ether, fentanyl, hydromorphone, levorphanol, Pethidine, methadone, morphine, oxycodone, morphine oxide ketone, Propoxyphene, buprenorphine, butorphanol, Wy-16225, nalbuphine and pentazocine). In addition, non-drug Analgesic techniques can with the compound conbined usage of one or more the present invention of administration. Such as, narcology (in backbone defeated note, nerve block), Neurological Surgery (neurolysis of CNS approach), nerve stimulation (transcutaneous electrical neural stimulation, backbone stimulate), physiatrics (physiatrics, orthopedic appliance, diathermy) or psychology (cognitive approach-syngignoscism, biofeedback or behavioral approach) method can also be used. Other suitable therapeutical agent or method generally describe at TheMerckManual, 17th edition, MarkH.Beers and RobertBerkow compiles, MerckResearchLaboratories, 1999, and Food and Drug Administration (FoodandDrugAdministration) websitewww.fda.gov, its whole content is incorporated to herein as a reference.
In another embodiment, other suitable therapeutical agent is selected from following:
(1) opioid analgesic agent, such as morphine, heroine, hydromorphone, morphine oxide ketone, levorphanol, levallorphan, methadone, Pethidine, fentanyl, Cocaine, morphine monomethyl ether, paracodin, oxycodone, hydrocodone, Propoxyphene, Nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
(2) NSAID (non-steroidal anti-inflammatory drug) (NSAID), such as acetylsalicylic acid, diclofenac, Fu Xina (diflusinal), R-ETODOLAC, fenbufen, fenoprofen, flufenisal, flurbiprofen, Ibuprofen BP/EP, indomethacin, Ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, Naproxen Base, nimesulide, nitro U-27182, Olsalazine, Taisho), Phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;
(3) barbiturate(s) tranquilizer, such as Amobarbital, somnifen, secondary Butobarbital, butalbital, Mephogarbital, metharbital, Methohexitone, Sodital, phenol veronal (phenobartital), secobarbital, Talbutal, Sai meter Le (theamylal) or thiobarbital (thiopental);
(4) there is sedative effect benzene two nitrogen, such as chlorine nitrogen, chlorine drawsAcid, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
(5) there is the H of sedative effect1Antagonist, such as diphenhydramine, pyrilamine, promethazine, chlorphenamine or chloreyclizine;
(6) tranquilizer, such as glutethimide, meprobamate, methaqualone or Dichloralphenazone;
(7) skeletal muscular relaxant, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
(8) nmda receptor antagonist, such as right first is muttered ((+)-3-hydroxy-N-methvl morphinan) or its metabolite, right hydroxyl is muttered ((+)-3-hydroxy-N-methvl morphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-((phosphonomethyl))-2 piperidine carboxylic acid, budipine (budipine), EN-3231 (MorphiDex (R), the combination dosage forms that morphine and right first are muttered), topiramate, neramexane or Pai Xinfute (perzinfotel) (comprises NR2B antagonist), such as ifenprodil, Qu Suoluo ground (traxoprodil) or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxyl-l-piperidyl]-l-hydroxyethyl-3, 4-bis-hydrogen-2 (1H)-quinolinone,
(9) alpha-adrenergic medicine, such as Doxazosin (doxazosin), tamsulosin (tamsulosin), clonidine, guanfacine, dexmetatomidine, modafinil or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinoline-2-base)-5-(2-pyridyl) quinazoline;
(10) tricyclics, such as Desipramine, imipramine, amitriptyline or nortriptyline;
(11) anticonvulsive drug, such as Carbamzepine, lamotrigine, topiratmate or valproate;
(12) tachykinin (NK) antagonist, particularly NK-3, NK-2 or NK-1 antagonist, such as ([��] R, 9R)-7-[3, two (trifluoromethyl) phenmethyl of 5-]-8, 910, 11-tetrahydrochysene-9-methyl-5-(4-aminomethyl phenyl)-7H-[l, 4] diazocino [2, l-g] [l, 7]-naphthyridine-6-13-diketone (TAK-637), 5-[[(2R, 3S)-2-[(lR)-l-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l, 2-bis-hydrogen-3H-l, 2, 4-triazole-3-ketone (MK-869), Aprepitant (aprepitant), draw how smooth, Dapitant or 3-[[2-methoxyl group-5-(trifluoromethoxy) phenyl]-methylamino-]-2-Phenylpiperidine (2S, 3S),
(13) muscarine antagonist, such as Oxybutynin, tolterodine, propiverine, trospium chloride (tropsiumchloride), darifenacin, YM-905 (solifenacin), for meter Wei Lin and Rinovagos;
(14) COX-2 selective depressant, such as celecoxib, rofecoxib, parecoxib, valdecoxib, draw and examine former times, L-791456 or Luo meter Kao former times (lumiracoxib);
(15) coal tar pain killer, particularly Paracetamol;
(16) Antipsychotic drug, such as droperidol, chlorpromazine, haloperidol, trilafon, thioridazine, mesoridazine, trifluoperazine, Fluphenazine, leoponex, olanzapine, risperidone, Ziprasidone, Quetiapine, Sertindole, Aripiprazole, rope how piperazine azoles, Bu Nanselin, Zomaril, Perospirone, raclopride, zotepine, than fluorine Nuo Xi (bifeprunox), Asenapine (asenapine), Lurasidone (lurasidone), amisulpride, balaperidone, palindore, Yi Liselin, Osanetant, Rimonabant, meclinertant, Miraxion (R) or Sha Lizuotan,
(17) capsaicin receptor agonist (such as resinferatoxin) or antagonist (such as capsazepine);
(18) beta-adrenergic medicine, such as Proprasylyte;
(19) local anesthetic, such as mexiletine;
(20) reflunomide, such as dexamethasone;
(21) 5-HT receptor stimulant or antagonist, particularly 5-HT1B/1DAgonist is Eletriptan, sumatriptan, naratriptan, Zomitriptan or Rizatriptan such as;
(22) 5-HT2A receptor antagonist, such as R (+)-��-(2,3-dimethoxy-phenyl)-l-[2-(4-fluorophenyl ethyl)]-4-piperidine carbinols (MDL-100907);
(23) cholinergic (nicotine) pain killer, such as isopropyl gram orchid (ispronicline) (TC-1734), (E)-N-methyl-4-(3-pyridyl)-3-butylene-l-amine (RJR-2403), (R)-5-(2-azetidinyl methoxyl group)-2-chloropyridine (ABT-594) or nicotine;
(24) tramadol
(25) PDEV inhibitor, such as 5-[2-oxyethyl group-5-(4-methyl-l-piperazinyl-alkylsulfonyl) phenyl]-l-methyl-3-n-propyl group-l, 6-bis-hydrogen-7H-pyrazoles also [4, 3-d] pyrimidin-7-ones (Virga), (6R, 12aR)-2, 3, 6, 7, 12, 12a-six hydrogen-2-methyl-6-(3, 4-methylenedioxyphenyl)-pyrazine also [2 ', l ': 6, l]-pyrido [3, 4-b] indoles-l, 4-diketone (IC-351 or Tadalafei), 2-[2-oxyethyl group-5-(4-ethyl-piperazin-l-base-l-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5, l-f] [l, 2, 4] triazine-4-ketone (Vardenafil), 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2, 6-bis-hydrogen-7H-pyrazoles also [4, 3-d] pyrimidin-7-ones, 5-(5-ethanoyl-2-propoxy--3-pyridyl)-3-ethyl-2-(1-sec.-propyl-3-azetidinyl)-2, 6-bis-hydrogen-7H-pyrazoles also [4, 3-d] pyrimidin-7-ones, 5-[2-oxyethyl group-5-(4-ethyl piperazidine-l-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2, 6-bis-hydrogen-7H-pyrazoles also [4, 3-d] pyrimidin-7-ones, 4-[(the chloro-4-methoxy-benzyl of 3-) amino]-2-[(2S)-2-(methylol) tetramethyleneimine-1-base]-N-(pyrimidine-2-base methyl) pyrimidine-5-methane amide, 3-(l-methyl-7-oxo-3-propyl group-6, 7-bis-hydrogen-lH-pyrazoles also [4, 3-d] pyrimidine-5-base)-N-[2-(l-crassitude-2-base) ethyl]-4-propoxy-benzsulfamide,
(26) �� t-2-2-delta ligand, such as gabapentin, lyrica, 3-methyl gabapentin, (l [��], 3 [��], 5 [��]) (3-amino methyl two ring [3.2.0]-3-in heptan base)-acetic acid, (3S, 5R)-3-amino methyl-5-methyl enanthic acid, (3S, 5R)-3-amino-5-methyl-enanthic acid, (3S, 5R)-3-amino-5-methyloctanoic acid, (2S, 4S)-4-(3-chlorophenoxy) proline(Pro), (2S, 4S)-4-(3-luorobenzyl)-proline(Pro), [(lR, 5R, 6S)-6-(amino methyl) two ring [3.2.0]-6-in heptan base] acetic acid, 3-(l-amino methyl-cyclohexyl methyl)-4H-[1,2,4] diazole-5-ketone, C-[1-(1H-TETRAZOLE-5-ylmethyl)-suberyl]-first amine, (3S, 4S)-(l-amino methyl-3,4-dimethylcyclopentyl)-acetic acid, (3S, 5R)-3-amino methyl-5-methyloctanoic acid, (3S, 5R)-3-amino-5-methyl nonanoic acid, (3S, 5R)-3-amino-5-methyl-sad, (3R, 4R, 5R)-3-amino-4,5-dimethyl enanthic acid and (3R, 4R, 5R)-3-amino-4,5-dimethyl are sad,
(27) cannaboid;
(28) metabotropic glutamate salt hypotype 1 acceptor (mGluRl) antagonist;
(29) thrombotonin cell reabsorption inhibitor, such as Sertraline, Sertraline metabolite go methyl Sertraline, fluoxetine, promise fluoxetine (fluoxetine removes first metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite to remove methyl citalopram, escitalopram, d, l-S-768, femoxetine, ifoxetine, cyanodothiepin, Litoxetine, dapoxetine, nefazodone, Cericlamine and trazodone;
(30) norepinephrine (nor-epinephrine) cell reabsorption inhibitor, such as maprotiline, Tymelvt, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, Wellbutrin, Wellbutrin metabolite hydroxyl Wellbutrin, nomifensine and viloxazine (Vivalan (R)), particularly selectivity norepinephrine cell reabsorption inhibitor such as Reboxetine, particularly (S, S)-Reboxetine;
(31) dual serotonin-norepinephrine cell reabsorption inhibitor, such as Venlafaxine, Venlafaxine metabolite O-DMV, clomipramine, clomipramine metabolite remove methyl clomipramine, duloxetine, Midalcipran and imipramine;
(32) nitric oxide synthase type (iNOS) inhibitor, such as S-[2-[(l-Iminoethyl) amino] ethyl]-L-homocysteine, S-[2-[(l-Iminoethyl)-amino] ethyl]-4, 4-dioxo-Cys, S-[2-[(l-Iminoethyl) amino] ethyl]-2-methyl-Cys, (2S, 5Z)-2-amino-2-methyl-7-[(l-Iminoethyl) amino]-5-heptenoic acid, 2-[[(lR, 3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl] sulphur generation] the chloro-S-pyridine nitrile of-S-, 2-[[(lR, 3S)-3-amino-4-hydroxy-l-(5-thiazolyl) butyl] sulphur generation]-4-chlorobenzonitrile, (2S, 4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl) phenyl] sulphur generation]-5-thiazole butanols, 2-[[(lR, 3S)-3-amino-4-hydroxy-l-(5-thiazolyl) butyl] sulphur generation]-6-(trifluoromethyl)-3-pyridine nitrile, 2-[[(lR, 3S)-3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulphur generation]-5-chlorobenzonitrile, N-[4-[2-(3-chlorophenylmethyl amino) ethyl] phenyl] thiophene-2-first amidine or GED,
(33) acetylcholinesterase depressant, such as E2020;
(34) prostaglandin E2 hypotype 4 (EP4) antagonist, such as 7V-[({ 2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo [4,5-c] pyridine-l-base) phenyl] ethyl } amino)-carbonyl]-4-methyl benzenesulfonamide or 4-[(15)-l-({ [the chloro-2-of 5-(3-fluorophenoxy) pyridin-3-yl] carbonyl } amino) ethyl] phenylformic acid;
(35) leukotrienes B4 antagonist; Such as l-(3-xenyl-4-ylmethyl-4-hydroxyl-chroman-7-base)-Cyclopentane carboxylic acid (CP-105696), 5-[2-(2-propyloic)-3-[6-(4-p-methoxy-phenyl)-5E-hexenyl]-oxygen phenoxyl]-valeric acid (ONO-4057) or DPC-11870
(36) 5-lipoxidase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxyl group-3,4,5,6-tetrahydrochysene-2H-pyrans-4-base]) phenoxy group-methyl]-l-methyl-2-quinolone (zD-2138) or 2,3,5-trimethylammonium-6-(3-pyridylmethyl)-l, 4-benzoquinones (CV-6504);
(37) sodium channel blockers, such as lignocaine;
(38) 5-HT3 antagonist, such as ondansetron; And pharmacologically acceptable salt and solvate.
The content of the other therapeutical agent being present in the present composition will comprise the amount of this therapeutical agent as administration in the composition of sole active usually by being no more than. Preferably, the amount of other in the compositions of the present invention therapeutical agent will comprise this reagent as in about 50% to 100% scope of the amount in the composition of sole therapy promoting agent being usually present in.
The compound of the present invention or its can also be incorporated to be coated with implantable medical device in composition by medicinal compositions, such as prosthese, artificial valve, blood vessel graft, support and conduit. Therefore, in yet another aspect, the present invention comprises the composition for being coated with implantable device, and it comprises as above and the compound of general the present invention described in classification herein and sub-class and be applicable to be coated with the carrier of described implantable device. , still in another, the present invention comprises a kind of implantable device, it scribbles as above and the compound of general the present invention described in classification herein and sub-class and be applicable to be coated with the carrier of described implantable device. Suitable coating and the general preparation of coating implantable device describe at United States Patent (USP) 6,099,562; 5,886,026; In 5,304,121. Coating is generally biocompatible polymeric material, such as hydrogel, poly-methyl sily oxide, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethene-vinyl acetate copolymer and mixture thereof. Coating can optionally be covered by the suitable external coating (EC) of fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its combination to give composition Co ntrolled release feature further.
Another aspect of the present invention relates to and suppresses in biological sample or experimenter one or more activity in NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9, the method comprises the compound to this snibject formula I or comprises the composition of described compound, or makes the compound of described biological sample contact I or comprise the composition of described compound. Term as used herein " biological sample " comprises, and is not limited to cell culture or its extract; The biopsy material obtained from Mammals or its extract; With blood, saliva, urine, ight soil, seminal fluid, tear or other body fluid or its extract.
In suppression biological sample, in NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9, one or more activity is applicable to various object well known by persons skilled in the art. The example of such object comprises, but is not limited to study biological and in pathological phenomenon sodium-ion channel; And compare and evaluate new sodium-ion channel inhibitor.
Embodiment
Universal method.1HNMR (400MHz) and13CNMR (100MHz) spectrum is at deuterate acetonitrile (CD3CN), chloroform-d (CDCl3) or methyl-sulphoxide-D6(DMSO) solution in obtains. Mass spectrum (MS) is that the AppliedBiosystemsAPIEXLC/MS system using and Phenomenex50 �� 4.60mmluna-5 �� C18 post being housed obtains. LC/MS elution system is the H of 1-99% or the 10-99% acetonitrile containing 0.035%v/v trifluoroacetic acid, 0.035%v/v formic acid, 5mMHCl or 5mM ammonium formiate2O solution, it may also be useful to the flow velocity of 3 or 15 minutes linear gradients and 12mL/ minute. Particle diameter is used to carry out silica gel chromatography for 230-400 object silica gel-60. Pyridine, methylene dichloride (CH2Cl2), tetrahydrofuran (THF) (THF), dimethyl formamide (DMF), acetonitrile (ACN), methyl alcohol (MeOH) and 1,4-bis-alkane is all from the AldrichSure-Seal bottle remained under drying nitrogen. Unless otherwise explanation, otherwise the reaction that magnetic stirring is all.
Trans-5a ', 6 ', 7 ', 8 ', 9 ', 9a '-six hydrogen-5'H-spiral shell [piperidines-4,4'-pyrrolo-[1,2-a] quinoxaline] dihydrochloride
Step 1:
By N-[(1R, 2R)-2-aminocyclohexyl] t-butyl carbamate (1.06g, 4.93mmol), sodium acetate (1.70g, 20.7mmol) He 2,5-dimethoxy-tetrahydrofuran (764 �� L, 5.91mmol) is mixing in acetic acid (10.6mL). This reaction mixture is heated 16 hours at 80 DEG C. Then, reaction mixture is steamed dry, and resistates is assigned between ethyl acetate and saturated sodium bicarbonate aqueous solution. It is separated each layer, and washs organic layer twice with saturated sodium chloride aqueous solution, through dried over sodium sulfate, and steam and dry obtain brown solid. Then, this solid is dissolved in the two alkane solution (10.3mL, 4.0M, 41.1mmol) of HCl, and makes it leave standstill 3 hours. Then, except desolventizing, trans-2-(1H-pyrroles's-1-base) the hexahydroaniline hydrochloride (989mg, 99%) in brown solid is obtained. ESI-MSm/z theoretical value: 164.1, measured value: 165.2 (M+1)+; Retention time: 0.27 minute (running 4 minutes).
Step 2:
By trans-2-(1H-pyrroles's-1-base) hexahydroaniline hydrochloride (989mg, 4.93mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (982mg, 4.93mmol) with toxilic acid (56.2mg, 0.493mmol) mixing in ethanol (12mL). Reacting by heating mixture 4 hours at 80 DEG C. Reaction mixture is cooled to room temperature, and evaporating solvent. Being dissolved in methylene dichloride by resistates, the 0-10% methyl alcohol being then used in methylene dichloride on 80g silica gel is gradient-purified, obtains trans-5a ', 6 ', 7 ', 8 ', 9 ', 9a '-six hydrogen-5 ' H-spiral shell [piperidines-4,4 '-pyrrolo-[1,2-a] quinoxaline]-1-carboxylic acid tert-butyl ester. ESI-MSm/z theoretical value: 345.2, measured value: 346.2 (M+1)+; Retention time: 1.63 minutes (running 4 minutes).
Step 3:
By trans-5a ', 6 ', 7 ', 8 ', 9 ', 9a '-six hydrogen-5 ' H-spiral shells [piperidines-4,4 '-pyrrolo-[1,2-a] quinoxaline]-1-carboxylic acid tert-butyl ester (0.311g, in the hydrogenchloride (2.0mL, 4.0M, 8.0mmol) 0.901mmol) being suspended in two alkane. Make reaction mixture sat 2 hours. Then, reaction mixture is steamed dry, obtain trans-5a ', 6 ', 7 ', 8 ', 9 ', 9a '-six hydrogen-5 ' H-spiral shell [piperidines-4,4 '-pyrrolo-[1,2-a] quinoxaline]. ESI-MSm/z theoretical value: 245.2, measured value: 246.3 (M+1)+; Retention time: 0.32 minute (running 3 minutes).
2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride
Step 1:
At 110 DEG C, heating 2,5-dimethoxy-tetrahydrofuran (15g, 113.5mmol), 2-chloroethyl amine hydrochloride (44.76g, 385.9mmol) and the mixture of sodium acetate (46.55g, 567.5mmol) in acetic acid (55mL). After 2 hr, this reactant is poured in salt solution, and use dichloromethane extraction product. With salt solution, saturated Na2CO3Again with salt water washing organism. Through dried over sodium sulfate organism and evaporate. (80g) is filled in, it may also be useful to hexane filters thick material as elutriant, obtains 1-(2-chloroethyl) pyrroles (10.1g, 69%) by Florisil.1HNMR (400MHz, CDCl3) �� 6.70 (t, J=1.9Hz, 2H), 6.18 (t, J=1.9Hz, 2H), 4.20 (t, J=6.5Hz, 2H), 3.73 (t, J=6.5Hz, 2H).
Step 2:
The ethanolic soln (7.3mL, 33%w/v, 77.15mmol) of 1-(2-chloroethyl) pyrroles (2.0g, 15.43mmol) with 33% first amine is mixed. At 90 DEG C, heating this mixture 16 hours, it under reduced pressure concentrated afterwards, obtain N-methyl-2-pyrroles-1-base-ethamine (2.19g, 88%), it is directly used in next reaction. ESI-MSm/z theoretical value: 124.1, measured value: 125.3 (M+1)+; Retention time: 0.22 minute (running 3 minutes).1HNMR (400MHz, CDCl3) �� 6.73-6.68 (m, 2H), 6.22-6.14 (m, 2H), 4.05 (t, J=5.9Hz, 2H), 2.94 (t, J=5.9Hz, 2H), 2.45 (s, 3H).
Step 3:
By N-methyl-2-pyrroles-1-base-ethamine (2.19g, 17.64mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.51g, 17.64mmol) and pTsOH H2O (0.334g, 1.76mmol) is mixing in ethanol (87.60mL), and heats 4 hours at 70 DEG C. Reactant is concentrated, and resistates is dissolved in methylene dichloride. With saturated NaHCO3Solution and salt water washing organism. Organism through dried over sodium sulfate and is evaporated. By silica gel chromatography purification of crude material, it may also be useful to containing the 0-10% methanol-eluted fractions in methylene dichloride of 2% triethylamine, obtain 2-methylspiro [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (4.2g, 78%). ESI-MSm/z theoretical value: 305.4, measured value: 306.3 (M+1)+; Retention time: 0.97 minute (running 3 minutes).1HNMR (400MHz, CDCl3) �� 6.55-6.52 (m, 1H), 6.15-6.11 (m, 1H), 5.92-5.89 (m, 1H), 3.92 (t, J=6.0Hz, 2H), 3.91-3.75 (m, 2H), 3.29 (t, J=6.0Hz, 2H), 3.26-3.12 (m, 2H), 2.36 (s, 3H), 2.10-1.99 (m, 2H), 1.83-1.69 (m, 2H), 1.47 (s, 9H).
Step 4:
Method A: mixing 2-methylspiro [3 in acetonitrile (10mL), 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylate (1.0g, 3.27mmol), salt of wormwood (497.7mg, 3.60mmol) and trifluoromethayl sulfonic acid ester; 5-(trifluoromethyl) dibenzothiophene-5-(1.32g, 3.27mmol). At 60 DEG C, heat this reaction mixture 16 hours. Reactant is steamed dry, and resistates is dissolved in methylene dichloride. With water and salt water washing organism, through dried over sodium sulfate and evaporation. By silica gel chromatography purification of crude material, with 0-50% eluent ethyl acetate in hexane, obtain 2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (812mg, 66%). ESI-MSm/z theoretical value: 373.2, measured value: 374.5 (M+1)+; Retention time: 1.21 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 6.52 (d, J=3.8Hz, 1H), 5.91 (d, J=3.8Hz, 1H), 3.98 (t, J=6.0Hz, 2H), 3.93-3.76 (m, 2H), 3.32 (t, J=6.0Hz, 2H), 3.26-3.08 (m, 2H), 2.36 (s, 3H), 2.11-1.99 (m, 2H), 1.81-1.65 (m, 2H), 1.47 (s, 9H).
Method B: by slow bubbling through the weight difference of solution and record metal tin, to the 2-methylspiro [3 in DMSO (164mL), 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (10.0g, 32.7mmol) adds FeSO47H2O (9.8mL, 1.0M, 9.8mmol), CF is then added3I (6.41g, 32.7mmol). With ice-water-bath cooling mixture, after through 15 minutes drip add H2O2(3.71mL, 30%w/v, 32.7mmol), keeps internal temperature < 20 DEG C simultaneously. This mixture is poured on the frozen water of 300mL, and extracts with EtOAc (2 �� 400mL). The organic phases washed with brine that will merge, through MgSO4Drying, filters and vacuum concentration. By the thick material of purification by column chromatography, with containing 2%iPr2The 0-10% methanol-eluted fractions in methylene dichloride of NEt, obtains 2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carboxylic acid tert-butyl ester (7.8g, 64%).
Step 5:
At room temperature, at the two alkane solution (26.10mL of 4MHCl, 4M, 104.4mmol) with in methyl alcohol (22mL), [3,4-pyrrolin is [1,2-a] pyrazine-1 also to stir 2-methyl-6-(trifluoromethyl) spiral shell, 4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (7.8g, 20.89mmol) 1 hour. Reaction mixture is steamed dry, and make the MTBE coevaporation of resistates and 100mL, obtain the 2 '-methyl-6 in yellow foam/solid '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride (7.23g, quantitatively). ESI-MSm/z theoretical value: 273.2, measured value: 274.5 (M+1)+; Retention time: 0.44 minute (running 3 minutes).
2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-first nitrile dihydrochloride
Step 1:
Under an argon, by Sulfuryl chloride isocyanate (590.9mg, 363.4tL, 4.175mmol) solution in tetrahydrofuran (THF) (2mL) slowly join and remain on-78 DEG C at (bath temperature) 2-methylspiro [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines] in the solution of-1 '-carboxylic acid tert-butyl ester (1020mg, 3.340mmol) in tetrahydrofuran (THF) (9mL). At-78 DEG C, reaction mixture is made to stir 1 hour. Then, by N, dinethylformamide (732.4mg, 775.8tL, 10.02mmol) slowly joins in cold reaction mixture. Then, this reaction mixture is made slowly to be warming up to room temperature. After at room temperature stirring 3 hours, dilute thick material with the tetrahydrofuran (THF) of 25mL, with the washing of 1M sodium hydroxide solution, then wash three times with saturated sodium chloride aqueous solution. Through dried over sodium sulfate organic layer, filter, and steam dry, obtain crude product. 80g silica gel uses the gradient-purified thick material of the hexane solution of 0-70% ethyl acetate, [3,4-pyrrolin is [1,2-a] pyrazine-1 also to obtain the 6-cyano group-2-methyl-spiral shell in white solid, 4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (280mg, 25%). ESI-MSm/z theoretical value: 330.2, measured value: 331.1 (M+1)+; Retention time: 0.94 minute.1HNMR (400MHz, CDCl3) �� 6.76 (d, J=4.0Hz, 1H), 5.97 (d, J=4.0Hz, 1H), 4.01 (t, J=6.0Hz, 2H), 3.98-3.76 (m, 2H), 3.36 (t, J=6.0Hz, 2H), 3.30-3.08 (m, 2H), 2.36 (s, 3H), 2.09-1.98 (m, 2H), 1.84-1.66 (m, 2H), 1.47 (s, 9H).
Step 2:
By 6-cyano group-2-methyl-spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (280mg, 0.8474mmol) it is dissolved in hydrochloric acid at two alkane (8mL, 4M, 32.00mmol) and two alkane (8mL) in mixture in. Make reaction mixture stir 30 minutes, then steam dry, obtain 2-methylspiro [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-first nitrile dihydrochloride (258mg, 99%) in white solid. ESI-MSm/z theoretical value: 230.2, measured value: 231.5 (M+1)+; Retention time: 0.50 minute (running 3 minutes).1HNMR (400MHz, D2O) �� 7.10 (d, J=4.2Hz, 1H), 6.59 (d, J=4.3Hz, 1H), 4.51 (t, J=6.4Hz, 2H), 4.02 (t, J=6.3Hz, 2H), (3.66-3.56 m, 2H), 3.49-3.36 (m, 2H), 2.95 (s, 3H), 2.69-2.59 (m, 2H), 2.54-2.40 (m, 2H).
N-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-2 '-carboxamide hydrochloride
Step 1:
To 6-(trifluoromethyl) spiral shell [3,4-dihydro-2 h-pyrrole is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carboxylic acid tert-butyl ester (600mg, 1.67mmol), THF (3mL) and Et3N (698 �� L, 5.01mmol) adds methyl isocyanate (199 �� L, 3.34mmol). Mixture is made at room temperature to stir 2 hours. Other Et is added in mixture3N (698 �� L, 5.01mmol) and methyl isocyanate (199 �� L, 3.34mmol), and at room temperature reaction stirred 3 days. Vapourisation under reduced pressure solvent. Resistates is dissolved in ethyl acetate (40mL), and washs with water (3 �� 10mL). Through dried over sodium sulfate organic layer, filter and vacuum concentration, obtain 2-(methylamino formyl radical)-6-(trifluoromethyl) spiral shell [3; 4-pyrrolin also [1; 2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (680mg, 97%). ESI-MSm/z theoretical value: 416.2, measured value: 417.4 (M+1)+; Retention time: 1.73 minutes (running 3 minutes).1HNMR (400MHz, DMSO) �� 7.14 (q, J=4.3Hz, 1H), 6.56 (d, J=3.4Hz, 1H), 6.03 (d, J=3.9Hz, 1H), 3.88 (t, J=5.4Hz, 2H), 3.73 (t, J=5.4Hz, 2H), 3.69-3.55 (m, 2H), 3.23-3.03 (m, 2H), 2.78-2.62 (m, 2H), 2.56 (d, J=4.4Hz, 3H), 1.76-1.60 (m, 2H), 1.40 (s, 9H).
Step 2:
To 2-(methylamino formyl radical)-6-(trifluoromethyl) spiral shell [3; 4-pyrrolin also [1; 2-a] pyrazine-1; 4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (0.66g; 1.6mmol) He in acetonitrile (5mL) add the solution (5.2mL of HCl in two alkane; 4.0M, 21mmol). Reaction mixture is at room temperature stirred 60 minutes. Vapourisation under reduced pressure solvent, obtains N-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-2-carboxamide hydrochloride (99%) in brown solid. ESI-MSm/z theoretical value: 316.2, measured value: 317.2 (M+1)+; Retention time: 0.77 minute (running 3 minutes).
Aforesaid method is used to synthesize following compound:
2 '-(2-methoxy ethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-phenmethyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-(2-methoxy ethyl)-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-ethyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
3 ', 3 '-dimethyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
3 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
4 ', 4 '-dimethyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 ', 3 '-dimethyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
3-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-cyclopropyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-(cyclopropyl methyl)-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 ', 3-dimethyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-methyl-6 '-(2,2,2-trifluoroethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-methyl-6 '-(perfluoro-ethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
N, N-dimethyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-2 '-methane amide,
2 '-(2,2,2-trifluoroethyl)-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] hydrochloride,
The fluoro-2 '-methyl of 3--6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2,2 '-dimethyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-4 '-carboxylate methyl ester,
2 '-(2,2-bis-fluoro ethyl)-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] hydrochloride,
2 '-cyclobutyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride,
2-(6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-2 '-yl) ethyl acetate and
6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-2 '-carboxylate methyl ester.
The fluoro-1-of 2,2,2-tri-(2-methylspiro [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base) second ketone dihydrochloride
Step 1:
At room temperature; by (2,2,2-trifluoroacetyl base) 2; 2; 2-trifluoro-acetate (910 �� L, 6.55mmol) drops to 2-methylspiro [3,4-pyrrolin also [1; 2-a] pyrazine-1; 4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (1.0g, 3.27mmol), pyridine (1.06mL, 13.10mmol) and CH2Cl2(6.5mL) in solution. At 35 DEG C, heat this mixture 2 hours. Reaction mixture is distributed in 1NHCl and CH2Cl2Between. It is separated each layer, and uses CH2Cl2(2X) aqueous layer extracted. Through the organism that dried over sodium sulfate merges, and filter. Concentrated filtrate, obtains 2-methyl-6-(2,2,2-trifluoroacetyl base) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carboxylic acid tert-butyl ester (1.38g, 94%) in light yellow solid. ESI-MSm/z theoretical value: 401.2, measured value: 402.5 (M+1)+; Retention time: 1.36 minutes.1HNMR (400MHz, CDCl3) �� 7.21 (dd, J=4.4,2.1Hz, 1H), 6.14 (d, J=4.5Hz, 1H), 4.34 (t, J=6.0Hz, 2H), 3.93 (s, 2H), 3.33 (t, J=6.0Hz, 2H), 3.19 (s, 2H), 2.39 (s, 3H), 2.13-2.05 (m, 2H), 1.79 (t, J=11.6Hz, 2H), 1.48 (s, 9H).
Step 2:
At room temperature; by hydrogenchloride (6.01mL; 4M; 24.07mmol) join 2-methyl-6-(2,2,2-trifluoroacetyl base) spiral shell [3; 4-pyrrolin also [1; 2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (1.38g, 3.44mmol) is at CH2Cl2(9.7mL) in the solution in. At room temperature, this mixture is stirred 1.5 hours. Under reduced pressure concentrated reaction mixture, obtains the fluoro-1-of 2,2,2-tri-(2-methylspiro [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base) the second ketone dihydrochloride (1.34g, 99%) in tawny solid. ESI-MSm/z theoretical value: 301.1, measured value: 302.5 (M+1)+; Retention time: 1.02 minutes.
2,2-dimethyl-1-(2-methylspiro [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base) the third-1-ketone dihydrochloride
Step 1:
At room temperature, by 2,2-dimethyl propylene acyl chlorides (1.22mL, 9.90mmol) join 2-methylspiro [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carboxylic acid tert-butyl ester (2.75g, 9.0mmol), in the mixture of DBN (1.22mL, 9.90mmol) and ethylene dichloride (6.9ml). At 115 DEG C, this mixture is made to stir 18 hours. This mixture is cooled to room temperature, is distributed in CH afterwards2Cl2And between 1NHCl. It is separated each layer, and washs organic layer with 1NNaOH. Through dried over sodium sulfate organic layer, filter and under reduced pressure concentrate. By column chromatography (0-100% ethyl acetate second ester/hexane) purifying resistates; obtain the 6-(2 in white-yellowish solid; 2-dimethyl propylene acyl group)-2-methyl-spiral shell [3; 4-pyrrolin also [1; 2-a] pyrazine-1; 4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (1.8g, 41%). ESI-MSm/z theoretical value: 389.3, measured value: 390.5 (M+1)+; Retention time: 1.46 minutes.
Step 2:
At room temperature; by hydrogenchloride (5.1mL; 4M; 20.22mmol) join 6-(2; 2-dimethyl propylene acyl group) [3,4-pyrrolin is [1,2-a] pyrazine-1 also for-2-methyl-spiral shell; 4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (1.75g, 4.49mmol) is at CH2Cl2(12.3mL) in the solution in. At room temperature, this mixture is stirred 1.5 hours. Under reduced pressure concentrated reaction mixture, obtains 2,2-dimethyl-1-(the 2-methylspiro [3 in tawny solid, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-6-base) the third-1-ketone dihydrochloride (1.8g, 99%). ESI-MSm/z theoretical value: 289.2, measured value: 290.5 (M+1)+; Retention time: 0.97 minute.
1-(2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) second ketone dihydrochloride
Step 1:
At 0 DEG C, to the 2-methylspiro [3 in METHYLENE CHLORIDE (73.5mL), 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (10g, N-bromosuccinimide (5.53g, 31.10mmol) is added by part in 32.74mmol). Reaction stirred at 0 DEG C. After 30 minutes, add other N-bromosuccinimide (291.4mg, 1.64mmol), and stir this reactant 1 hour. Use 0.5MNa2S2O3(135mL) diluting reaction thing, and remove aqueous phase. Organic layer is washed with salt solution (135mL). Through dried over sodium sulfate organic layer, filter and vapourisation under reduced pressure solvent, obtain the bromo-2-methyl-spiral shell [3 of 6-in red viscous liquid, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester, its in next step without the need to being further purified. 1HNMR (400MHz, DMSO) �� 6.09 (d, J=3.7Hz, 1H), 5.99 (d, J=3.7Hz, 1H), 3.78-3.65 (m, 4H), 3.27 (t, J=6.0Hz, 2H), 3.17-2.92 (m, 2H), 2.21 (s, 3H), 2.03-1.93 (m, 2H), 1.65-1.53 (m, 2H), 1.40 (s, 9H) .ESI-MSm/z theoretical value: 383.1, measured value: 386.0 (M+1)+; Retention time: 1.13 minutes (running 3 minutes).
Step 2:
Use N2Blow and sweep the bromo-2-methyl-spiral shell [3 of 6-, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (2g, 5.2mmol) with N-cyclohexyl-N-methyl-cyclohexyl amine (1.67mL, 7.81mmol) the solution in 1,4-bis-alkane (8.0ml) 5 minutes. Add 1-vinyloxy group butane (7.04mL, 52.04mmol), Pd (dba)3(1.078g, 1.04mmol) and tri-tert phosphine (642.0 �� L, 2.60mmol), and at 80 DEG C in pressurized vessel reacting by heating thing 5 hours. Ethyl acetate is used to filter reactant by plug of celite. Vapourisation under reduced pressure solvent. Pass through silica gel chromatography; 1-100% ethyl acetate gradient in hexane is used to carry out purification of crude product; obtain the 6-ethanoyl-2-methyl-spiral shell [3 in yellow solid; 4-pyrrolin also [1; 2-a] pyrazine-1; 4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (672.1mg, 1.93mmol, 37%).1HNMR (400MHz, DMSO) �� 7.04 (d, J=4.1Hz, 1H), 6.12 (d, J=4.2Hz, 1H), 4.17 (t, J=6.0Hz, 2H), 3.83-3.68 (m, 2H), 3.21 (t, J=6.0Hz, 2H), 3.17-2.91 (m, 2H), 2.31 (s, 3H), 2.24 (s, 3H), 2.07-1.97 (m, 2H), 1.72-1.59 (m, 2H), 1.41 (s, 9H) .ESI-MSm/z theoretical value: 347.2, measured value: 348.5 (M+1)+; Retention time: 0.95 minute (running 3 minutes).
Step 3:
To 6-ethanoyl-2-methyl-spiral shell [3; 4-pyrrolin also [1; 2-a] pyrazine-1; 4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (300mg; 0.86mmol) and METHYLENE CHLORIDE (1.7mL) in be added in two alkane hydrogenchloride (1.60mL; 4M, 6.40mmol). At room temperature, reaction stirred 0.5 hour. Vapourisation under reduced pressure solvent, obtains 1-(2-methylspiro [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base) the second ketone dihydrochloride in light green solid with quantitative yield. ESI-MSm/z theoretical value: 247.2, measured value: 248.2 (M+1)+; Retention time: 0.17 minute (running 3 minutes).
Aforesaid method is used to synthesize following compound:
1-(2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) the third-1-ketone dihydrochloride,
2-methyl isophthalic acid-(2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) third-1-ketone dihydrochloride,
Cyclopropyl (2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) first ketone dihydrochloride,
(2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) (phenyl) first ketone dihydrochloride,
1-(3 ', 3 '-dimethyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji)-2,2,2-trifluoroethanone dihydrochloride,
1-(3 ', 3 '-dimethyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) second ketone dihydrochloride,
1-(3 ', 3 '-dimethyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-7 '-Ji) second ketone dihydrochloride,
The fluoro-1-of 2,2,2-tri-(2 ', 4 ', 4 '-trimethylammonium-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) second ketone dihydrochloride,
The fluoro-1-of 2,2,2-tri-(2 ', 4 ', 4 '-trimethylammonium-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-7 '-Ji) second ketone dihydrochloride,
1-(2 ', 4 ', 4 '-trimethylammonium-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) second ketone dihydrochloride,
1-(2 ', 3 '-dimethyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji)-2,2,2-trifluoroethanone dihydrochloride,
The fluoro-1-of 2,2,2-tri-(3 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) second ketone dihydrochloride,
The fluoro-1-of 2,2,2-tri-(4 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) second ketone dihydrochloride,
1-(2 ', 4 '-dimethyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji)-2,2,2-trifluoroethanone dihydrochloride, and
(2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) (1-methyl cyclopropyl) first ketone.
2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-8 '-first nitrile dihydrochloride
Step 1:
To 2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (1.86g, 5.0mmol) solution in acetonitrile (50ml) adds N-bromine succinimide (930.4mg, 5.25mmol). At room temperature it is uniformly mixed thing to spend the night. Vapourisation under reduced pressure solvent. Resistates is distributed between ethyl acetate and water. It is separated each layer, and by ethyl acetate (2x) aqueous layer extracted. The organic layer washed with brine that will merge, through MgSO4Dry and concentrate to dry. By column chromatography (10-20% ethylacetate-hexane) purification of crude material, obtain the product (1.7g, 75%) in light yellow solid. ESI-MSm/z theoretical value: 451.1, measured value: 452.1 (M+1)+; Retention time: 1.59 minutes (running 3 minutes).
Step 2:
Use N2Blow and sweep tertiary butyl 8-bromo-2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylicesters (1.67g, 3.7mmol) and the mixture of dicyano zinc (234.9 �� L, 3.7mmol) in DMF (10mL) 5 minutes. Add Pd (PPh3)4(427.6mg, 0.37mmol). At 150 DEG C, in sealing microwave vial, heated mixt spends the night. This mixture is distributed between ethyl acetate and water. It is separated each layer. By ethyl acetate (3x) aqueous layer extracted. All organic layers are merged, with water (3x), salt water washing, through MgSO4Drying, filters and concentrates to dry. By column chromatography (10-20%EtOAc/ hexane) purification of crude material, obtain 8-cyano group-2-methyl-6-(trifluoromethyl) spiral shell [3 in white solid, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (510mg, 35%). ESI-MSm/z theoretical value: 398.2, measured value: 399.3 (M+1)+; Retention time: 1.56 minutes (running 3 minutes).
Step 3:
To 8-cyano group-2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (278.9mg, HCl (2mL 0.7mmol) being added in two alkane in the solution in DCM (4mL), 4M, 8.0mmol). At room temperature, this mixture is stirred 30 minutes. Evaporating solvent, and thick material is directly used in next step without the need to being further purified. ESI-MSm/z theoretical value: 298.1, measured value: 299.5 (M+1)+; Retention time: 0.88 minute (running 3 minutes).
6 '-chloro-2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride
Step 1:
At 0 DEG C, to the 2-methylspiro [3 in methylene dichloride (50.00mL), 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (5g, add trifluoromethanesulfchloride chloride (3.64mL, 34.38mmol) in 16.37mmol), and spend the night from 0 DEG C to stirring at room temperature reactant. With methylene dichloride diluting reaction thing, and wash with water. It is separated each layer, and through dried over sodium sulfate organism, filters and concentrate. By silica gel chromatography purifying resistates, adopt 10-100% eluent ethyl acetate in hexane, obtain the chloro-2-methyl-spiral shell [3 of 6-in yellow solid, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (4.3g, 77%). ESIMSm/z theoretical value: 339.2, measured value: 340.3 (M+1)+; Retention time: 1.13 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 6.01 (d, J=3.8Hz, 1H), 5.91 (d, J=3.7Hz, 1H), 3.77 (t, J=6.1Hz, 2H), 3.34 (s, 2H), 3.24 (s, 2H), 2.34 (s, 3H), 2.03 (d, J=13.1Hz, 2H), 1.74 (t, J=11.1Hz, 2H), 1.47 (s, 9H).
Step 2:
By HCl (1.84mL, the two alkane solution of 4M, 7.34mmol) join the chloro-2-methyl-spiral shell [3 of 6-, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines] in the solution of-1 '-carboxylic acid tert-butyl ester (624mg, 1.84mmol) in methylene dichloride (2mL), and stir 1 hour at 40 DEG C. Reactant is steamed dry, obtain 6 '-chloro-2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride (quantitatively), its can use and without the need to being further purified. ESI-MSm/z theoretical value: 239.1, measured value: 240.3 (M+1)+; Retention time: 0.22 minute (running 3 minutes).
6 '-cyano group-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-2 '-carboxylate hydrochloride
Step 1:
Vinyl chloroformate (328.2 �� L, 3.43mmol) is joined spiral shell [3,4-dihydro-2 h-pyrrole is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carboxylic acid tert-butyl ester (500mg, 1.72mmol) and K2CO3In (474.3mg, 3.43mmol) solution in acetonitrile (5.0mL), and at room temperature reaction stirred is spent the night. Acetonitrile is used to filter reactant, and vapourisation under reduced pressure solvent. Compound is dissolved in ethyl acetate, and with 1N hydrochloric acid and salt water washing. Through dried over sodium sulfate organic layer, filter and under reduced pressure concentrate, obtain 3 ' in amber oily matter, 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1,2 '-dicarboxylic acid 1-tert-butyl 2 '-second ester (395mg, 63%), its in next step without the need to being further purified. ESI-MSm/z theoretical value: 363.2, measured value: 364.3 (M+1)+; Retention time: 1.78 minutes (running 3 minutes).
Step 2:
At-78 DEG C, under a nitrogen, by N-(oxo methylene radical) sulphonamide chlorine (23.9 �� L, 0.27mmol) solution in THF (200.0 �� L) slowly joins 3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1, in the solution of the 2 '-dicarboxylic acid 1-tertiary butyl 2 '-second ester (100mg, 0.27mmol) in THF (1.0mL). This reaction mixture is stirred 1 hour at-78 DEG C. Then, by N, dinethylformamide (39.9 �� L, 0.51mmol) slowly joins in cold reaction mixture. Then, reaction mixture is made slowly to be warming up to room temperature. Filter reactant, and by anti-phase preparation-LC-MS (10-99%CH3CN/H2O), it may also be useful to HCl modifier purifying, obtain 6 '-cyano group-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1,2 '-dicarboxylic acid 1-butyl 2 '-second ester. ESI-MSm/z theoretical value: 388.2, measured value: 389.3 (M+1)+; Retention time: 1.82 minutes (running 3 minutes).
Step 3:
By the two alkane solution (8.7mL of 4NHCl, 34.7mmol) join 6 '-cyano group-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1, the solution of 2 '-dicarboxylic acid 1-tert-butyl 2 '-second ester (0.27mmol) in methylene dichloride (5mL), and at 40 DEG C, stir this mixture 1 hour. Reaction mixture is steamed dry, obtain 6 '-cyano group-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-2 '-carboxylate hydrochloride. ESI-MSm/z theoretical value: 288.2, measured value: 289.3 (M+1)+; Retention time: 0.75 minute (running 3 minutes).
8 '-fluoro-2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride
Step 1:
To 2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (5.60g, 15.0mmol) solution in acetonitrile (50mL) adds NBS (2.80g, 15.8mmol). At room temperature, this mixture overnight is stirred. Except desolventizing, and resistates is distributed between EtOAc and water. By EtOAc (2x) aqueous layer extracted. The organic layer merged with salt water washing, through MgSO4Dry and concentrate to dry. By column chromatography (10-20%EtOAc-Hex) purification of crude material, obtain 8-bromo-2-methyl-6-(trifluoromethyl) spiral shell [3 in light yellow solid, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (5.40g, 73%). ESI-MSm/z theoretical value: 452.3, measured value: 454.5 (M+1)+; Retention time: 1.60 minutes (running 3 minutes).
Step 2:
With argon purge 8-bromo-2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines] solution of-1 '-carboxylic acid tert-butyl ester (15.0g, 33.2mmol) in THF (200mL) 5 minutes. This mixture is cooled to-78 DEG C, drips afterwards and add nBuLi (42.5mL, 1.6M, 68mmol). At-78 DEG C, it is uniformly mixed thing 30 minutes, drips the solution adding the fluoro-benzsulfamide (20.9g, 66.3mmol) of N-(benzenesulfonyl)-N-in THF (100mL) afterwards. Mixture is made to be warming up to ambient temperature overnight. With saturated NH4Cl aqueous solution cancellation reaction mixture. It is separated each layer, and by EtOAc (2x) aqueous layer extracted. Merge organic layer, and use salt water washing, through MgSO4Drying, filters and concentrates to dry. Add CH2Cl2, and via solids removed by filtration. Filtrate is concentrated to dry, and by column chromatography (10-20%EtOAc-Hex) purifying resistates, obtain 8-fluoro-2-methyl-6-(trifluoromethyl) spiral shell [3 in light brown oil thing, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (5.52g, 43%), it solidifies when standing. ESI-MSm/z theoretical value: 391.4, measured value: 392.5 (M+1)+; Retention time: 1.35 minutes (running 3 minutes).
Step 3:
To at CH2Cl2(2mL) fluoro-2-methyl-6-(trifluoromethyl) spiral shell of the 8-in [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (310mg, HCl (2.0mL is added in 0.80mmol), 4M, 8.0mmol) solution in 1,4-bis-alkane. At room temperature, reaction mixture is made to stir 1 hour. Under reduced pressure remove volatile matter, obtain 8-fluoro-2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also] dihydrochloride (290mg, 99%) of pinkiness solid. ESI-MSm/z theoretical value: 291.1, measured value: 292.3 (M+1)+; Retention time: 0.75 minute (running 3 minutes).
8 '-chloro-2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride
Step 1:
At-78 DEG C, to 8-bromo-2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (5.00g, 11.1mmol) solution in anhydrous THF (125mL) slowly adds nBuLi (8.84mL, 2.5M, 22.1mmol). At-78 DEG C, make reaction mixture stir 20 minutes, drip the solution adding 1,1,1,2,2,2-hexachloroethane (5.36g, 22.7mmol) in THF (12mL) afterwards. Make reaction mixture slowly be warming up to room temperature, and stir and spend the night. Add saturated aqueous ammonium chloride solution (100mL) cancellation reaction mixture. Under reduced pressure remove volatile matter to half volume. With the remaining waterborne suspension of EtOAc (2 �� 100mL) extraction. Through the organic layer that dried over sodium sulfate merges, filter and under reduced pressure concentrate, obtain thick brown oil. Pass through silica gel column chromatography: 10-20%EtOAc/ hexane gradient purification of crude product, obtain 8-chloro-2-methyl-6-(trifluoromethyl) spiral shell [3 in yellow oil, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (2.40g, 53%), its crystallization when standing. ESI-MSm/z theoretical value: 407.2, measured value: 407.9 (M+1)+; Retention time: 1.70 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 6.47 (s, 1H), 3.97 (t, J=5.5Hz, 4H), 3.28 (s, 2H), 3.13 (s, 2H), 2.51-2.28 (m, 5H), 1.93 (d, J=13.7Hz, 2H), 1.47 (d, J=9.5Hz, 9H).
Step 2:
To 8-chloro-2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carboxylic acid tert-butyl ester (750mg, 1.84mmol) at CH2Cl2(2mL) 1: 1 trifluoroacetic acid (2.0mL, 26mmol) adding preparation in the solution in is at CH2Cl2(2mL) solution in. After at room temperature stirring 2 hours, slowly add saturated sodium bicarbonate aqueous solution (75mL). This mixture is extracted with EtOAc (2 �� 75mL). Merge organic layer, through dried over sodium sulfate, filter and under reduced pressure concentrate, [3,4-pyrrolin is [1,2-a] pyrazine-1 also to obtain 8-chloro-2-methyl-6-(trifluoromethyl) spiral shell in tawny solid, 4 '-piperidines] (555mg, 98%). ESI-MSm/z theoretical value: 307.1, measured value: 307.9 (M+1)+; Retention time: 1.12 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 9.72 (s, 1H), 9.38 (s, 1H), 6.49 (s, 1H), 3.98 (t, J=5.6Hz, 2H), 3.36 (d, J=11.6Hz, 2H), 3.26 (d, J=6.1Hz, 4H), 2.78 (s, 2H), 2.40 (s, 3H), 2.11 (d, J=14.4Hz, 2H), 1.69 (s, 2H).
2 '-methyl-6 ', 7 '-bis-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]
Step 1:
At room temperature, by FeSO47H2O (803 �� L, 1.00M, 0.803mmol) join 2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-carboxylic acid tert-butyl ester (1.00g, 2.68mmol) and DMSO (15mL) mixture in. Then, in container, load CF3I (gas), drips afterwards and adds H2O2(304 �� L, 30%w/v, 2.68mmol). At room temperature, mixture is stirred and spends the night, distributed between ethyl acetate and water afterwards. It is separated each layer, and by ethyl acetate (3x) aqueous layer extracted. The organics washed with brine that will merge, through dried over sodium sulfate, filters and concentrates. By column chromatography (0-100% ethyl acetate/hexane) purifying resistates, obtain two (trifluoromethyl) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carboxylic acid tert-butyl ester of 2-methyl-6,7-. ESI-MSm/z theoretical value: 441.2, measured value: 442.5 (M+1)+; Retention time: 1.36 minutes (running 3 minutes).
Step 2:
Two for 2-methyl-6,7-(trifluoromethyl) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carboxylic acid tert-butyl ester (from step 1) is collected in CH2Cl2(2mL) in, and HCl (1.7mL, 4M, 6.8mmol) is added. Make this mixture stir 30 minutes, afterwards it is under reduced pressure concentrated. By residual collection in ethyl acetate, and with saturated NaHCO3Solution washing, then uses salt water washing. Through dried over sodium sulfate organic layer, filter and concentrate, obtain two (trifluoromethyl) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also] of 2-methyl-6,7-(22mg, 2%, through 2 steps). ESl-MSm/z theoretical value: 341.1, measured value: 342.3 (M+1)+; Retention time: 1.29 minutes.
2 '-methyl-6 '-(methyl sulphonyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]
Step 1:
At 0 DEG C, at CH2Cl2(30mL) 2-methylspiro [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-benzyl carboxylate (3.00g, 8.84mmol) adds NBS (1.57g, 8.84mmol) by part. At 0 DEG C, stirred reaction mixture 2 hours. Add other NBS (157mg), and at 0 DEG C, stirred reaction mixture 15 minutes (repeating 6 times again until starting raw material exhausts). Use 0.5MNa2S2O3(30mL) diluted reaction mixture, and remove aqueous phase. Organic phase is washed with salt solution (30mL). Through dried over sodium sulfate organic layer, filter and vapourisation under reduced pressure solvent. Pass through column chromatography, it may also be useful at CH2Cl2In the gradient-purified crude product of 0-30% ethyl acetate, obtain 6-bromo-2-methyl-spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-benzyl carboxylate (2.34g, 63%) in emulsifiable paste shape solid. ESl-MSm/z theoretical value: 417.1, measured value: 418.1 (M+1)+; Retention time: 1.49 minutes (running 3 minutes).1HNMR (400MHz, DMSO) �� 7.43-7.26 (m, 5H), 6.09 (d, J=3.7Hz, 1H), 5.99 (d, J=3.7Hz, 1H), 5.08 (s, 2H), 3.89-3.74 (m, 2H), 3.68 (t, J=5.8Hz, 2H), 3.27 (t, J=5.8Hz, 2H), 3.22-2.99 (m, 2H), 2.21 (s, 3H), 2.09-1.94 (m, 2H), 1.73-1.52 (m, 2H).
Step 2:
At 90 DEG C, pressurized vessel heats methane-sulfinic acid sodium (293mg, 2.87mmol), the bromo-2-methyl-spiral shell [3 of 6-, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-benzyl carboxylate (1.00g, 2.39mmol), CuI (296mg, 1.55mmol) and DMSO (5mL) mixture 20 hours. This mixture is cooled, and is distributed between ether (10mL) and water (10mL). Separation organic layer, and by ether (3 �� 5mL) aqueous layer extracted. The organic layer merged with salt solution (2 �� 10mL) washing, through dried over sodium sulfate, filters and vacuum concentration. Pass through column chromatography, it may also be useful at CH2Cl2In the gradient-purified crude product of 0-50% ethyl acetate, obtain 2-methyl-6-methyl sulphonyl-spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-benzyl carboxylate (520mg, 52%) in white solid. ESl-MSm/z theoretical value: 417.2, measured value: 418.3 (M+1)+; Retention time: 1.27 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.45-7.30 (m, 5H), 6.88 (d, J=4.1Hz, 1H), 6.01 (d, J=3.9Hz, 1H), 5.15 (s, 2H), 4.28-4.15 (m, 2H), 4.09-3.89 (m, 2H), 3.40-3.16 (m, 4H), 3.10 (s, 3H), 2.37 (s, 3H), 2.20-2.02 (m, 2H), 1.89-1.66 (m, 2H).
Step 3:
Under nitrogen atmosphere; to 2-methyl-6-methyl sulphonyl-spiral shell [3; 4-pyrrolin also [1; 2-a] pyrazine-1; 4 '-piperidines]-1 '-benzyl carboxylate (520mg; solution in EtOH (13mL) 1.25mmol) adds the palladium-carbon (66mg, 0.062mmol) of 10%. Under a hydrogen atmosphere, at room temperature stirred reaction mixture 16 hours. By plug of celite filtering mixt, and vapourisation under reduced pressure solvent, obtain the 2-methyl-6-methyl sulphonyl-spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also] (342mg, 97%) in white-yellowish solid. ESl-MSm/z theoretical value: 283.1, measured value: 284.3 (M+1)+; Retention time: 0.30 minute (running 3 minutes).
3-methyl-4-(methyl sulfamyl) phenylformic acid
Step 1:
By 4-amino-3-methyl-phenylformic acid (4.00g, 26.5mmol) solution in dense HCl (15mL) is cooled to 0 DEG C in ice bath, drip afterwards and add Sodium Nitrite (1.97g, 910 �� L, 28.6mmol) the solution in water (5mL), keeps temperature lower than 5 DEG C simultaneously. By SO2Bubbling is by acetic acid (60mL) and CuCl2The solution of (889mg, 6.62mmol) 20 minutes, adds cold diazo solution afterwards. Reaction mixture is stirred 1 hour, is poured on ice afterwards. Solid collected by filtration, and wash with water. Further drying solid, obtains 4-chlorosulfonyl-3-methyl-phenylformic acid (2.30g, 37%).1HNMR (400MHz, DMSO) �� 7.81 (d, J=7.8Hz, 1H), 7.74-7.66 (m, 2H), 2.57 (s, 3H).
Step 2:
At room temperature, 4-chlorosulfonyl-3-methyl-phenylformic acid (0.99g, 4.2mmol), first amine (2.0mL, 33%w/v, 21mmol) and triethylamine (1.8mL, 13mmol) 45 minutes is stirred. Evaporation reaction mixture, and the oily matter obtained is distributed between ethyl acetate and 1NHCl. Separation organic layer, and wash with the 1NHCl of another part, then use salt water washing. Through dried over sodium sulfate organism, and evaporate, obtain 3-methyl-4-(methyl sulfamyl) phenylformic acid (841mg, 87%). ESl-MSm/z theoretical value: 229.0, measured value: 230.5 (M+1)+; Retention time: 0.64 minute (running 3 minutes).
Aforesaid method is used to synthesize following compound:
4-(N-ethylsulfamovl)-3-tolyl acid, 4-(N-cyclopropyl sulfamyl)-3-tolyl acid, 4-(N-isopropylsulfamoyl base)-3-tolyl acid and 4-(N, N-dimethylamino alkylsulfonyl)-3-tolyl acid.
7-(ethyl (methyl) amino) pyrazoles also [1,5-a] pyrimidine-3-carboxylic acid
Step 1:
To 7-hydroxypyrazoles also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester (0.95g, 4.6mmol) at POCl3Stirred suspension in (8.0mL, 86mmol) adds xylidine (0.8 �� L, 0.006mmol), and at 80 DEG C, heats this mixture 2 hours. This mixture slowly is poured on ice, and with 1NNaOH, pH is adjusted to carefully��7, then, use solid Na2CO3It is adjusted to pH10. Then, mixture is extracted with methylene dichloride (3x). Merge organism, use salt water washing, dry (MgSO4) and steam dry. Use hexane abrasive solid, obtain 7-chlorine pyrazoles also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester (260mg, 25%) in tawny solid. ESl-MSm/z theoretical value: 225.0, measured value: 226.5 (M+1)+; Retention time: 0.87 minute (running 3 minutes).
Step 2:
To 7-chlorine pyrazoles also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester (68mg, 0.30mmol) at CH3Solution in CN (1mL) adds N-methyl ethyl-amine (18mg, 0.30mmol), and is uniformly mixed thing at ambient temperature 16 hours. Evaporating mixture, and by column chromatography (dichloromethane solution of 0-10%MeOH) purifying resistates, obtain solid. By solid collection in EtOH (0.5mL) and water (0.1mL), add NaOH (12mg, 0.30mmol) afterwards. At 50 DEG C, it is uniformly mixed thing 4 hours. With dense HCl by the pH regulator to 4 of this mixture, and except desolventizing. Resistates and MeOH (3x) are evaporated jointly, obtains 7-(ethyl (methyl) amino) pyrazoles also [1,5-a] pyrimidine-3-carboxylic acid. ESl-MSm/z theoretical value: 220.1, measured value: 221.5 (M+1)+; Retention time: 0.29 minute (running 3 minutes).
Aforesaid method is used to synthesize following compound:
7-(ethylamino) pyrazoles also [1,5-a] pyrimidine-3-carboxylic acid, 7-(sec.-propyl amino) pyrazoles also [1,5-a] pyrimidine-3-carboxylic acid, 7-(ethyl (methyl) amino)-5-methylpyrazole also [1,5-a] pyrimidine-3-carboxylic acid, 5-methyl-7-(tetramethyleneimine-1-base) pyrazoles also [1,5-a] pyrimidine-3-carboxylic acid and 7-(ethylamino)-5-methylpyrazole also [1,5-a] pyrimidine-3-carboxylic acid.
4-(1-hydroxyl-1-methyl-ethyl)-3-methyl-phenylformic acid
Bromo-for 4-3-methyl-phenylformic acid (3.96g, 18.4mmol) is dissolved in tetrahydrofuran (THF) (100mL), and this solution is cooled to-78 DEG C. The n-Butyl Lithium (16.2mL, 2.5M, 41mmol) added in hexane is dripped through 20 minutes. At-78 DEG C, make reaction mixture stir 30 minutes, then add mode add acetone (1.35mL, 18.4mmol) to drip. At-78 DEG C, make reaction mixture stir 30 minutes, then make it be warming up to room temperature. Afterwards, with the 1M aqueous sodium hydroxide solution diluted reaction mixture of 100mL. Abandon organic layer, then make water layer be acid with 4M aqueous hydrochloric acid. Then, water layer it is extracted with ethyl acetate 3 times. Through the extract that dried over sodium sulfate merges, then steam dry. The gradient-purified thick material of the 0-10% methyl alcohol being used in methylene dichloride further on silica gel, obtains 4-(1-hydroxyl-1-methyl-ethyl)-3-methyl-phenylformic acid (1.51g, 42%).1HNMR (400MHz, DMSO) �� 12.74 (s, 1H), 7.68 (dd, J=3.9,2.5Hz, 2H), 7.55 (d, J=8.7Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H), 1.51 (s, 6H).
Aforesaid method is used to synthesize following compound:
4-(1-hydroxycyclopent base)-3-tolyl acid, 4-(1-hydroxycyclopent base) phenylformic acid, 4-(1-hydroxy-cyclohexyl)-3-tolyl acid, 4-(1-hydroxy-cyclohexyl) phenylformic acid, the fluoro-4-of 3-(1-hydroxy-cyclohexyl) phenylformic acid and 4-(1-hydroxy-cyclohexyl)-3-methoxybenzoic acid.
5-isopropoxy-6-picoline formic acid
Step 1:
2-methyl-3-pyridol (8.3g, 76.1mmol) is suspended in acetonitrile (125mL). Through 1 hour, the solution of NBS (27.7g, 155.6mmol, 2.05equiv) in acetonitrile (275mL) is added drop-wise in this suspension. By this mixture reflux 1.5 hours. This mixture concentrated, and by column chromatography (DCM) purifying resistates, obtain the 4,6-bis-bromo-2-picoline-3-alcohol (15.8g, 78%) in yellow solid.1HNMR (300MHz, DMSO-d6) 2.41 (s, 3H), 7.70 (s, 1H), 9.98 (s, 1H).
Step 2:
Bromo-for 4,6--bis-2-picoline-3-alcohol (15.8g, 59.4mmol) is dissolved in THF (200mL). This solution is cooled to-78 DEG C, and drip add n-BuLi (hexane solution of 50mL, 125mmol, 2.5M), simultaneously keep temperature lower than-78 DEG C. Mixture is made to stir 2 hours at such a temperature. With this mixture of water (50mL) cancellation, and neutralize with 2NHCl. With methylene dichloride (2x) cancellation aqueous mixture. Organic layer drying (the Na that will merge2SO4) and concentrated, obtain the 6-bromo-2-picoline-3-alcohol (10.5g, 95%) in yellow oil.1H-NMR (300MHz, DMSO-d6) 2.29 (s, 3H), 7.08 (d, 1H), 7.26 (d, 1H), 10.08 (s, 1H).
Step 3:
Bromo-for 6-2-picoline-3-alcohol (10.5g, 55.9mmol) is dissolved in DMF (100mL). By K2CO3(19.3g, 139.6mmol) and 2-N-PROPYLE BROMIDE (13.1ml, 139.6mmol) join in this solution, and heated mixt spends the night at 100 DEG C. This mixture is poured in the mixture of water and EtOAc (200mL). It is separated each layer, and by EtOAc (2x) aqueous layer extracted. Organic layer drying (the Na that will merge2SO4) and concentrated. By column chromatography (0-20% ethyl acetate/heptane) purification of crude oily matter, obtain the 6-bromo-3-isopropoxy-2-picoline (10.9g, 85) in yellow oil.1H-NMR (300MHz, CDCl3) 1.42 (d, 6H), 2.48 (s, 3H), 4.65 (m, 1H), 7.20 (d, 1H), 8.04 (d, 1H).
Step 4:
In Berghoff reactor, by bromo-for 6-3-isopropoxy-2-picoline (2.00g, 8.70mmol), PdCl2(PPh3)2(0.18g, 0.26mmol) and Et3N (1.8ml, 13.04mmol) joins in MeOH (5.2mL) and acetonitrile (20mL). In this reactor, load 10barCO (g), and at 60 DEG C heated overnight. Enriched mixture, and resistates is distributed between DCM and water. Be separated each layer, and with salt water washing organic layer and dry (Na2SO4). Mixture is concentrated, and by purification by column chromatography, obtains 5-isopropoxy-6-picoline methyl-formiate (1.3g, 71%).1H-NMR (300MHz, CDCl3) 1.40 (d, 6H), 2.53 (s, 3H), 3.98 (s, 3H), 4.62 (m, 1H), 7.12 (d, 1H), 7.98 (d, 1H).
Step 5:
5-isopropoxy-6-picoline manthanoate (1.3g, 6.22mmol) is dissolved in THF/ water 2:1 (9mL). Add LiOH*H2O (0.26g, 6.22mmol), and at room temperature stir this mixture overnight. Mixture is poured in the mixture of water and EtOAc, and it is separated each layer. Make with 2NHCl aqueous layer acidified to pH4, and extract with EtOAc (2x). Organism drying (the Na that will merge2SO4) and concentrated, obtain 5-isopropoxy-6-picoline formic acid (860mg, 74%) in beige solid.1H-NMR (300MHz, DMSO-d6) 1.31 (d, 6H), 4.73 (m, 1H), 7.44 (d, 1H), 7.86 (d, 1H) .1HNMR (400MHz, DMSO) �� 12.61 (s, 1H), 7.88 (d, J=8.5Hz, 1H), 7.44 (d, J=8.7Hz, 1H), 4.74 (dt, J=12.0,6.0Hz, 1H), 2.37 (s, 3H), 1.32 (d, J=6.0Hz, 6H).
Aforesaid method is used to synthesize following compound:
5-methoxyl group-6-picoline formic acid.
4-isopropoxy-3-methoxybenzoic acid
Step 1:
At-78 DEG C, at N2Under balloon, tert-butyl lithium (2.14mL, 1.6M, 3.43mmol) is added drop-wise in the solution of 4-bromo-1-isopropoxy-2-anisole (400mg, 1.63mmol) in THF (6.0mL). At-78 DEG C, make this mixture stir 1 hour, it is added dropwise to the CO being included in THF (2.0mL) afterwards2In the flask of (1.80g, 40.8mmol) (solid, dry ice). When this mixture is warming up to room temperature so that it is stir and (note: CO for 30 minutes2Gas is overflowed). Add water (20mL), and under reduced pressure remove volatile matter. What make with 1NHCl to obtain is aqueous layer acidified to pH��1-2, and extracts this mixture by ethyl acetate (3 �� 15mL). The organism merged with salt water washing, through dried over sodium sulfate, filters and concentrates, and obtains 4-isopropoxy-3-methoxybenzoic acid (>=94% is pure, 310mg, 85%) in white solid. ESI-MSm/z theoretical value: 210.1, measured value: 210.9 (M+1)+; Retention time: 1.23 minutes.1HNMR (400MHz, DMSO) �� 12.63 (s, 1H), 7.53 (dd, J=8.4,2.0Hz, 1H), 7.44 (d, J=2.0Hz, 1H), 7.04 (d, J=8.7Hz, 1H), 4.67 (dt, J=12.1,6.0Hz, 1H), 3.78 (s, 3H), (1.28 d, J=6.0Hz, 6H).
3-methoxyl group-4-(2-(trifluoromethoxy) oxyethyl group) phenylformic acid
Step 1:
At N2Under, in the sodium hydride (200mg, 5.0mmol) in DMF (6mL), add 4-hydroxyl-3-methoxyl group-methyl benzoate (920mg, 5.0mmol), and stir this mixture 10 minutes. Then, drip and add trifluoromethanesulfonic acid 2-(trifluoromethoxy) second ester (1.2g, 4.6mmol), then at room temperature stir this solution 2 hours, stir 2 hours at 50 DEG C afterwards. This mixture is condensed into solid, and by the CH of residual collection at 50mL2Cl2In, afterwards with salt solution (20mL) washing, through MgSO4Drying, and by column chromatography (0-25%EtOAc/ hexane) purifying, obtain 3-methoxyl group-4-(2-(trifluoromethoxy) oxyethyl group) methyl benzoate in white solid. ESI-MSm/z theoretical value: 294.1, measured value: 295.3 (M+1)+; Retention time: 1.63 minutes (running 3 minutes).
Step 2:
3-methoxyl group-4-(2-(trifluoromethoxy) oxyethyl group) methyl benzoate (step 1 obtains) is dissolved in THF (5mL), and add the suspension of LiOH (550mg, 23mmol) in water (5mL). This mixture of strong stirring, and heat 6 hours at 60 DEG C, concentrated subsequently to half volume. Add water (5mL), and extract mixture with ether (1 �� 10mL). With 4NHCl Acidified aqueous layer to pH2. The mixture obtained is extracted by ethyl acetate (3 �� 10mL), and washing (1 �� 10mLH2O, 1 �� 10mL salt solution) wash the organism merged, through MgSO4Drying, and evaporation, obtain 3-methoxyl group-4-(2-(trifluoromethoxy) oxyethyl group) phenylformic acid (1.0g, 82%) in white solid. ESI-MSm/z theoretical value: 280.1, measured value: 281.3 (M+1)+; Retention time: 1.34 minutes (running 3 minutes).
Uncle 4--butoxy-3-methoxybenzoic acid
Step 1:
By Vanillin (500mg, 3.29mmol), Boc2O (1.74g, 7.97mmol) and Sc (OTf)3(0.080g, 0.16mmol) is mixed in methylene dichloride (5mL). At room temperature, reaction mixture is made to stir 24 hours. Add water (5mL) and methylene dichloride (5mL), and it is separated two-phase. By methylene dichloride (3 �� 5mL) aqueous layer extracted, and stir the organism merged with 10% potassium hydroxide aqueous solution, until not observing the initial substance (TLC, 40% ethyl acetate in hexane) of all remnants in organic phase. Separation two-phase, then, washs dichloromethane layer twice with saturated sodium chloride aqueous solution, through dried over sodium sulfate, filters and steams dry, obtain the uncle 4--butoxy-m-methoxybenzaldehyde (130mg, 19%) in yellow oil. Rf=0.66 (SiO2, 40% ethyl acetate in hexane); ESI-MSm/z theoretical value: 208.1, measured value: 209.2 (M+1)+. Retention time: 0.96 minute (running 6 minutes).
Step 2:
Uncle 4--butoxy-m-methoxybenzaldehyde (130mg, 0.62mmol) is suspended in the mixture of two alkane (520 �� L) and potassium hydroxide (6.5mL, 0.20M, 1.3mmol). Add KMnO4(150mg, 0.93mmol), and strong stirring reactant 16 hours. Filter reaction mixture, then concentrate to 3mL. Add hydrochloric acid (1M, 4mL), filter the throw out that (after leaving standstill 15 minutes) obtains, and with 1MHCl and a small amount of water washing, obtain the uncle 4--butoxy-3-methoxyl group-phenylformic acid (68mg, 49%) in white solid. Rf=0.23 (SiO2, 40% ethyl acetate in hexane); ESI-MSm/z theoretical value: 224.1, measured value: 225.2 (M+1)+. Retention time: 1.66 minutes (running 3 minutes).1HNMR (400MHz, DMSO) �� 12.80 (s, 1H), 7.66-7.41 (m, 2H), 7.09 (d, J=8.8Hz, 1H), 3.78 (s, 3H), 1.32 (s, 9H).
Aforesaid method is used to synthesize following compound:
4-tert.-butoxy-3-tolyl acid is synthesized by 4-hydroxy-3-methyl phenyl aldehyde, by 2-fluoro-4,5-dimethoxy benzaldehyde synthesis 2-fluoro-4,5-dimethoxybenzoic acid, by 4-hydroxyl-Benzaldehyde,2-methoxy synthesis uncle 4--butoxy-O-Anisic Acid, by the fluoro-4-hydroxy benzaldehyde synthesis 4-tert.-butoxy-2-fluorobenzoic acid of 2-, and synthesize 4-tert.-butoxy phenylformic acid by 4-hydroxy benzaldehyde.
4-ethyl-3-methoxybenzoic acid
Two alkane (25mL) stir 4-bromo-3-methoxybenzoic acid (2.49g, 10.9mmol) and Pd (dppf) Cl2(158mg0.216mmol) mixture, and add Et2Zn (hexane solution of 22mL, 1M, 22mmol). Reacting by heating mixture 1 hour at 70 DEG C. This mixture is cooled to room temperature, and with MeOH (1.1mL) cancellation. With ethyl acetate (20mL) diluting soln, and wash with 1NHCl (10mL). The organism merged with salt water washing, through dried over sodium sulfate and steam dry, obtain 4-ethyl-3-methoxybenzoic acid. ESI-MSm/z theoretical value: 180.1, measured value: 179.1 (M-1)-; Retention time: 1.77 minutes (running 3 minutes).
4-(isopropelsulfonyl)-3-tolyl acid
Step 1:
At-78 DEG C, butyllithium (16mL, 1.6M, 26mmol) is added drop-wise in the mixture of the bromo-3-methyl-phenylformic acid (2.5g, 12mmol) of 4-and THF (63mL). At-78 DEG C, make this mixture stir 30 minutes, drip the solution adding 2-sec.-propyl disulphanes base propane (1.7g, 12mmol) in THF (2mL) afterwards. Make this mixture stir 30 minutes at-78 DEG C, then at room temperature stir 30 minutes. Afterwards, with the 1M aqueous sodium hydroxide solution diluted reaction mixture of 100mL. Abandon organic layer, make water layer be acid with 4M aqueous hydrochloric acid. Then, it is extracted with ethyl acetate water layer 3 times. By the extract of merging through dried over sodium sulfate, then steam dry. Pass through column chromatography, it may also be useful to the gradient-purified thick material of the 0-5%MeOH in methylene dichloride, obtain 4-(isopropyisulfanyl)-3-tolyl acid (870mg, 18%). MSm/z theoretical value: 210.3, measured value: 211.2 (M+1)+. Retention time: 2.32 minutes (running 3 minutes).
Step 2:
At 25 DEG C, by 3-chlorobenzene peroxyformic acid (3-Chlorobenzenecarboperoxoicacid) (930mg, 4.2mmol) join in the mixture of 4-(isopropyisulfanyl)-3-tolyl acid (250mg, 1.2mmol) and methylene dichloride (5.0mL). At 25 DEG C, this mixture is made to stir 2 hours, afterwards by its vacuum concentration. White solid matter is collected in methylene dichloride, and carries out column chromatography (0-2%MeOH/ methylene dichloride), obtain 4-isopropelsulfonyl-3-methyl-phenylformic acid (90mg, 31%) in white solid. ESI-MSm/z theoretical value: 242.3, measured value: 243.2 (M+1)+. Retention time: 1.57 minutes (running 3 minutes).1HNMR (400MHz, DMSO) �� 13.50 (s, 1H), 8.50-7.66 (m, 3H), 3.50-3.47 (m, 1H), 2.67 (s, 3H), 1.19 (d, J=1.16Hz, 6H).
Aforesaid method is used to synthesize following compound:
4-(isopropelsulfonyl)-2-tolyl acid and 4-(ethylsulfonyl)-3-tolyl acid,
4-(2-hydroxyl third-2-base)-3-methoxybenzoic acid
Bromo-for 4-3-methoxybenzoic acid (2.00g, 8.67mmol) is dissolved in THF (50mL), and this solution is cooled-78 DEG C. The n-BuLi (7.6mL, 2.5M, 19mmol) added in hexane is dripped through 15 minutes. At-78 DEG C, make reaction mixture stir 30 minutes, then add mode add acetone (640 �� L, 8.9mmol) to drip. At-78 DEG C, make reaction mixture stir 30 minutes, then make it be warming up to room temperature. Then, with the 1M aqueous sodium hydroxide solution diluted reaction mixture of 100mL. Abandon organic layer, make water layer be acid with 4M aqueous hydrochloric acid. Then, it is extracted with ethyl acetate water layer 3 times. By the extract of merging through dried over sodium sulfate, then steam dry. By column chromatography, utilize the gradient-purified thick material of 0-5% methyl alcohol in methylene dichloride methane, obtain 4-(2-hydroxy propane-2-base)-3-tolyl acid (618mg, 34%). ESI-MSm/z theoretical value: 210.1, measured value: 209.1 (M-1)-; Retention time: 0.68 minute (running 3 minutes).
The fluoro-4-isopropoxy phenylformic acid of 3-
Step 1:
K is added in the fluoro-4-hydroxyl-methyl benzoate (2.00g, 11.8mmol) of the 3-in DMF (12.5mL)2CO3(6.50g, 47.0mmol), then adds 2-iodopropane (2.35mL, 23.5mmol). At 60 DEG C, heat this mixture 1.5 hours. EtOAc is used to filter this mixture, and vapourisation under reduced pressure filtrate. Resistates is dissolved in EtOAc, and with water and salt water washing. Through dried over sodium sulfate organic layer, filter and under reduced pressure concentrate, obtain the fluoro-4-isopropoxy methyl benzoate of 3-. ESI-MSm/z theoretical value: 212.1, measured value: 213.3 (M+1)+. Retention time: 1.70 minutes (running 3 minutes).
Step 2:
Mixing 3-fluoro-4-isopropoxy methyl benzoate (from step 1), 1,4-bis-alkane (31mL) and NaOH (31mL, 1.0M, 31mmol), and at 80 DEG C, heat this mixture 20 minutes. Vapourisation under reduced pressure solvent. Crude mixture is dissolved in water, and washs with EtOAc (3x). Abandon the organism merged. By aqueous layer acidified, and extract with EtOAc (3x). Through dried over sodium sulfate organic layer, filter and under reduced pressure concentrate, obtain the fluoro-4-isopropoxy-phenylformic acid (1.25g, 72%) of 3-in white solid. ESI-MSm/z theoretical value: 198.1, measured value: 199.3 (M+1)+. Retention time: 1.34 minutes (running 3 minutes).
Aforesaid method is used to synthesize following compound:
The fluoro-4-isopropoxy phenylformic acid of 2-and 4-isopropoxy-3-tolyl acid, 3-cyano group-4-isopropoxy phenylformic acid and 4-isopropoxy-3-(trifluoromethyl) phenylformic acid.
4-(tert. butylsulfonyl) phenylformic acid
Step 1:
Mixing 4-ethyl fluoro benzoate (1.5g, 8.9mmol) and tert-butylsulfanyl sodium (2.00g, 17.8mmol) in DMF (10mL). At 80 DEG C, reacting by heating mixture 2 hours. Form a large amount of throw out, add other 15mLDMF, and reaction mixture is stirred 20 hours at 80 DEG C again. Reaction mixture is distributed between ethyl acetate (100mL) and water (100mL). Abandon organic layer, and make water layer be acid with 4M hydrochloric acid. It is extracted with ethyl acetate water layer twice. Through the extract that dried over sodium sulfate merges, filter, and steam dry, obtain 4-(the tertiary fourth sulphur base) phenylformic acid in colorless oil. ESI-MSm/z theoretical value: 210.3, measured value: 211.1 (M+1)+. Retention time: 1.74 minutes (running 3 minutes).
Step 2:
4-(tertiary fourth sulphur base) phenylformic acid (from step 1) is dissolved in AcOH (10mL), and is joined in reaction mixture by hydrogen peroxide (5.0mL30%w/w, 52mmol). The mixture that obtains is heated 2 hours at 80 DEG C. Then, make reaction mixture be cooled to room temperature, and with the diluted ethyl acetate of the water of 50mL and 100mL. It is separated each layer, and it is extracted with ethyl acetate water layer. Through the acetic acid ethyl ester extract that dried over sodium sulfate merges, filter and steam dry, obtain white solid. Then, this white solid is dissolved in methylene dichloride, and steams dry. Then, drying solid 16 hours under vacuo, obtain the 4-tert-butyl sulfonyl benzoic acid (2.2g, 92%) in white solid. ESI-MSm/z theoretical value: 242.1, measured value: 243.1 (M+1)+. Retention time: 1.15 minutes (running 3 minutes).1HNMR (400MHz, DMSO) �� 8.18 (d, J=8.0Hz, 2H), 7.94 (d, J=7.6Hz, 2H), 1.25 (s, 9H).
Aforesaid method is used to synthesize following compound:
4-(ethylsulfonyl) phenylformic acid
4-(iso-butylsulfonyl) phenylformic acid
Step 1:
At room temperature, by K2CO3(1.23g, 8.92mmol) joins in the mixture of 4-sulphur alkylbenzoic acid methyl esters (1.00g, 5.95mmol), 1-bromo-2-methyl-propane (970 �� L, 8.92mmol) and DMF (10mL). At room temperature, make mixture stir 4 hours, filter out solid afterwards. Wash solid by ethyl acetate, then abandon. By the filtrate distribution of merging between ethyl acetate (100mL) and water (100mL). It is separated each layer, and with salt water washing organic layer, through dried over sodium sulfate, filters and concentrate, obtain 4-(isobutylthio) methyl benzoate (82%) of transparent oily matter. ESI-MSm/z theoretical value: 224.1, measured value: 225.2 (M+1)+. Retention time: 1.59 minutes (running 3 minutes).
Step 2:
At room temperature, m-CPBA (3.59g, 15.6mmol) is joined 4-(isobutyl-sulphur alkyl) methyl benzoate (1.00g, 4.46mmol) at CH2Cl2(20mL) in the solution in. This mixture is made to stir 2 hours, afterwards by its vacuum concentration. Resistates is carried out column chromatography (0-100% ethyl acetate/hexane), obtains 4-(iso-butylsulfonyl) methyl benzoate. ESI-MSm/z theoretical value: 256.1, measured value: 257.2 (M+1)+; Retention time: 1.96 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 8.23 (d, J=8.4Hz, 2H), 8.00 (d, J=8.3Hz, 2H), 3.98 (s, 3H), 3.02 (d, J=6.5Hz, 2H), 2.25 (dp, J=13.3,6.6Hz, 1H), 1.07 (d, J=6.7Hz, 6H).
Step 3:
At 80 DEG C, the mixture of heating 4-iso-butylsulfonyl methyl benzoate (1.00g, 3.90mmol), NaOH (10mL, 1.0M, 10mmol) and 1,4-bis-alkane (10mL) 1.5 hours. This mixture is cooled to room temperature, afterwards vacuum concentration. Solid residue is collected in water, and with ethyl acetate washing, is abandoned. Use 1NHCl Acidified aqueous layer, and extract by ethyl acetate (2x). The organism merged with salt water washing, through dried over sodium sulfate, and vacuum concentration. Resistates is carried out column chromatography (0-100% ethyl acetate/hexane), obtains 4-(iso-butylsulfonyl) phenylformic acid (98%). ESI-MSm/z theoretical value: 242.1, measured value: 243.2 (M+1)+; Retention time 1.73 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 8.30 (d, J=8.3Hz, 2H), 8.05 (d, J=8.3Hz, 2H), 3.03 (d, J=6.5Hz, 2H), 2.27 (dt, J=13.3,6.6Hz, 1H), 1.08 (d, J=6.7Hz, 6H).
3-(methylol)-4-isopropoxy-phenylformic acid
Step 1:
2-iodopropane (11.1mL, 111mmol) is added in 3-formyl radical-4-hydroxyl-methyl benzoate (10.0g, 55.5mmol), salt of wormwood (30.7g, 222mmol) and DMF (63mL). At 60 DEG C, heat this mixture 18 hours. Use ethyl acetate (200mL) filtering mixt, and vapourisation under reduced pressure solvent. Resistates is dissolved in ethyl acetate (150mL), and washs with water (3 �� 75mL) and saturated sodium chloride aqueous solution (1 �� 75mL). Through dried over sodium sulfate organic layer, filter and vapourisation under reduced pressure solvent, obtain 3-formyl radical-4-isopropoxy-methyl benzoate (98%) in yellow viscous liquid. ESI-MSm/z theoretical value: 222.2, measured value: 223.3 (M+1)+; Retention time: 1.51 minutes (running 3 minutes).1HNMR (400MHz, DMSO) �� 10.35 (s, 1H), 8.23 (d, J=2.3Hz, 1H), 8.17 (dd, J=8.8,2.3Hz, 1H), 7.39 (d, J=8.9Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J=6.0Hz, 6H).
Step 2:
3-formyl radical-4-isopropoxy-methyl benzoate (180mg, 0.81mmol) is dissolved in tetrahydrofuran (THF) (4.8mL), and adds LiBH4(35mg, 1.6mmol). At room temperature, reaction stirred 30 minutes, afterwards, with methyl alcohol (3mL) cancellation. By adding saturated sodium bicarbonate aqueous solution (3mL) neutralization reactant, then extract by ethyl acetate (3 �� 10mL). The organism merged with the washing of saturated sodium chloride aqueous solution (1 �� 10mL), through dried over sodium sulfate, filter and vapourisation under reduced pressure solvent, obtain 3-(hydroxymethyl)-4-isopropoxy-methyl benzoate (99%) in viscous liquid. ESI-MSm/z theoretical value: 224.3, measured value: 225.3 (M+1)+; Retention time: 1.26 minutes (running 3 minutes).1HNMR (400MHz, DMSO) �� 8.09 (s, 1H), 7.89 (d, J=8.6Hz, 1H), 7.13 (d, J=8.6Hz, 1H), 5.25 (t, J=5.6Hz, 1H), 4.86-4.68 (m, 1H), 4.54 (d, J=5.6Hz, 2H), 3.87 (s, 3H), (1.35 d, J=6.0Hz, 6H).
Step 3:
To 3-(methylol)-4-isopropoxy-methyl benzoate (180mg, 0.80mmol) He in 1,4-bis-alkane (1.895mL) add sodium hydroxide (2.1mL, 1.0M, 2.1mmol), and at 80 DEG C, heat this mixture 50 minutes. Vapourisation under reduced pressure solvent. Crude mixture is dissolved in water (10mL), and with ethyl acetate (3 �� 10mL) washing, is abandoned. Use hcl acidifying water layer. By ethyl acetate (3 �� 10mL) aqueous layer extracted. Through the organism that dried over sodium sulfate merges, filter and vapourisation under reduced pressure solvent, obtain 3-(hydroxymethyl)-4-isopropoxy-phenylformic acid (89%) in white solid. ESI-MSm/z theoretical value: 210.2, measured value: 211.3 (M+1)+; Retention time: 1.01 minutes (running 3 minutes).
Aforesaid method is used to synthesize following compound:
4-oxyethyl group-3-(hydroxymethyl) phenylformic acid, 4-(2-hydroxy-2-methyl propoxy-)-3-tolyl acid, 4-isopropoxy-3-methoxyl group-5-tolyl acid, 5-isobutoxy pyridine carboxylic acid, 5-(isopentyloxy) pyridine carboxylic acid, 5-isopropoxy-4-picoline formic acid.
3-methyl-4-(trimethylene oxide-3-base) phenylformic acid
Step 1:
At N2Under, in pressure bottle, by (4-cyano group-2-methyl-phenyl) boric acid (1.75g, 10.87mmol), two iodine nickel (102mg, 0.326mmol), (1S, 2S) own-1-alcohol hydrochloride (50mg, 0.33mmol) and NaHMDS (2.01g, 11.0mmol) of-2-amino ring mixing in Virahol (10mL). Add the solution of 3-iodine trimethylene oxide (1.00g, 5.44mmol) in Virahol (1mL). Bottle is immersed in 90 DEG C of oil baths of preheating, and stir 2 hours, then cool, with ethanol (20mL) dilution, through diatomite filtration, concentrated, then absorb over celite, and by silica gel column chromatography (0-60%EtOAc/ hexane) purifying, obtain 3-methyl-4-(trimethylene oxide-3-base) cyanobenzene (616mg in white solid, 3.556mmol, 65.42%). ESI-MSm/z theoretical value: 173.1, measured value: 174.3 (M+1)+; Retention time: 1.09 minutes (running 3 minutes).
Step 2:
To 3-methyl-4-(trimethylene oxide-3-base) cyanobenzene (500mg in ethanol (7.5mL), NaOH (3.0mL is added in 2.89mmol), 5M, 15mmol), and this mixture is immersed in the oil bath of 85 DEG C. Heated mixt, and stir 1 hour, concentrated, then dilute by ethyl acetate (20mL). Add 6NHCl (��3mL) and regulate pH to 6. By ethyl acetate (2 �� 20mL) aqueous layer extracted, the organic layer then merged with salt solution (10mL) washing, through MgSO4Drying also concentrates, and obtains white solid, by it with triturated under ether, obtains the mixture (2:3, according to NMR) of acid 3-methyl-4-(trimethylene oxide-3-base) phenylformic acid (500mg, 14%) and acid amides. ESI-MSm/z theoretical value: 192.2, measured value: 193.3 (M+1)+; Retention time: 0.87 minute (running 3 minutes).
5-isopropoxy-6-methoxypyridine formic acid
Step 1:
In the solution of 2-chloro-6-iodine pyridine 3-alcohol (5.00g, 19.57mmol) in DMF, add the salt of wormwood (5.409g, 39.14mmol) of fine grinding, then add 2-N-PROPYLE BROMIDE (4.814g, 3.675mL, 39.14mmol). At 70 DEG C, reaction mixture is stirred and spends the night. Under reduced pressure, this reaction mixture concentrated. Resistates is dissolved/is suspended in EtOAc (75mL), and wash with water (1 �� 75mL). Further by EtOAc (1 �� 75mL) aqueous layer extracted. Merge two organic layers, through dried over sodium sulfate, filter and under reduced pressure concentrate, obtain yellow oil, passed through silica gel column chromatography: 0-30%EtOAc/ hexane gradient purifying, obtain the iodo-3-isopropoxy-pyridine (5.68g, 97.%) of the chloro-6-of 2-of transparent colourless rare oily matter. ESI-MSm/z theoretical value: 296.9, measured value: 298.4 (M+1)+; Retention time: 1.74 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.55 (d, J=8.3Hz, 1H), 6.90 (d, J=8.3Hz, 1H), 4.53 (dt, J=12.1,6.1Hz, 1H), 1.39 (d, J=6.1Hz, 6H).
Step 2:
Iodo-for chloro-for 2-6-3-isopropoxy-pyridine (2.00g, 6.722mmol) is dissolved in DMF (15mL). Add Zn (CN)2(592mg, 5.04mmol), and this mixture of nitrogen bubble, add Pd (PPh afterwards3)4(600mg, 0.519mmol). Reactive system is sealed, and heats 30 minutes under microwave irradiation at 100 DEG C. By reaction mixture EtOAc (75mL) dilution, and with the washing of saturated sodium bicarbonate aqueous solution (75mL), then wash with salt solution (75mL). Through dried over sodium sulfate organic layer, filter and under reduced pressure concentrate, obtain clear oil thing, passed through silica gel column chromatography: 0-30%EtOAc/ hexane purifying, obtain the chloro-5-isopropoxy of the 6--pyridine-2-first nitrile (1.17g of transparent colorless oil, 88%), its crystallization when standing. ESI-MSm/z theoretical value: 196.0, measured value: 197.3 (M+1)+; Retention time: 1.46 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.61 (d, J=8.4Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 4.67 (dt, J=12.1,6.1Hz, 1H), 1.45 (d, J=6.1Hz, 6H).
Step 3:
Chloro-for 6-5-isopropoxy-pyridine-2-first nitrile (1.10g, 5.59mmol) is dissolved in methyl alcohol (11mL). The solution of HCl (11mL, 4M, 44.00mmol) in 1,4-bis-alkane is added in this solution. At 70 DEG C, reaction mixture is stirred and spends the night. Reaction mixture is cooled to room temperature, and under reduced pressure concentrates. Residual solid is suspended in EtOAc (75mL), and washs with saturated sodium bicarbonate aqueous solution (1 �� 75mL). Through dried over sodium sulfate organic layer, filter and under reduced pressure concentrate. Being passed through silica gel column chromatography: 0-50%EtOAc/ hexane purifying, obtain the chloro-5-isopropoxy-pyridine-2-carboxylic acids methyl esters (894mg, 69%) of 6-of transparent colorless oil, it is crystallization when standing. ESI-MSm/z theoretical value: 229.1, measured value: 230.3 (M+1)+; Retention time: 1.23 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 8.06 (d, J=8.4Hz, 1H), 7.25 (d, J=8.5Hz, 1H), 4.68 (dt, J=12.1,6.1Hz, 1H), 3.97 (s, 3H), 1.44 (d, J=6.1Hz, 6H).
Step 4:
Chloro-for 6-5-isopropoxy-pyridine-2-carboxylic acids methyl esters (330mg, 1.44mmol) is dissolved in two alkane (12mL), and adds the solution of sodium methylate (5.75mL, 0.5M, 2.87mmol) in methyl alcohol. At 140 DEG C, reacting by heating thing 1.5 hours under microwave irradiation. Add water (52 �� L, 2.9mmol), and at 100 DEG C, reacting by heating mixture 30 minutes under microwave irradiation. With 1NHCl solution (50mL) diluted reaction mixture, and extract with EtOAc (2 �� 50mL). Merge organic layer, through dried over sodium sulfate, filter and under reduced pressure concentrate, obtain 5-isopropoxy-6-methoxypyridine-2-carboxylic acid (300mg, 98%) in beige solid. ESI-MSm/z theoretical value: 211.1, measured value: 211.9 (M+1)+; Retention time: 0.97 minute (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.83 (d, J=8.1Hz, 1H), 7.17 (d, J=8.1Hz, 1H), 4.72-4.61 (m, 1H), 4.06 (s, 3H), 1.45 (t, J=7.4Hz, 7H).
Uncle 5--butoxy pyridine carboxylic acid
Step 1:
DMF (6mL) (contributing to stirring) is added in the NaOtBu (1.57g, 16.4mmol) in HMPA (6mL). Add 5-fluorine pyridine-2-first nitrile (1.00g, 8.19mmol), and stir this dark mixture and spend the night. With water (100mL) dilution mixture thing, with DCM (3 �� 50mL) extraction, and with water (50mL) and saturated NaHCO3The aqueous solution (50mL) washs organism, through MgSO4Drying, evaporates and by column chromatography (0-50%EtOAc/hex) purifying, obtains uncle 5--butoxy pyridine-2-first nitrile (0.90g, 62%) in yellow solid. ESI-MSm/z theoretical value: 211.1, measured value: 211.9 (M+1)+; Retention time: 0.97 minute (running 3 minutes).1HNMR (400MHz, CDCl3) �� 8.38 (dd, J=2.7,0.5Hz, 1H), 7.67-7.56 (m, 1H), 7.41-7.31 (m, 1H), 1.52-1.38 (m, 10H).
Step 2:
In 5-tert.-butoxy pyridine-2-first nitrile (751mg, 4.26mmol) in ethanol (10mL), add NaOH (4.262mL, 5M, 21.31mmol), and this mixture is immersed 85 DEG C add in heating bath. Heated mixt, and stir 1 hour, concentrated, then dilute by ethyl acetate (50mL). Add 10mL salt solution and the 6NHCl (being adjusted to pH6) of��3mL. Separation organic layer, through MgSO4Drying also concentrates, and obtains the uncle 5--butoxy pyridine-2-carboxylic acids (820mg, 98%) in yellow solid. ESI-MSm/z theoretical value: 195.1, measured value: 196.1 (M+1)+; Retention time: 0.62 minute (running 3 minutes).1HNMR (400MHz, DMSO) �� 12.74 (s, 1H), 8.29 (d, J=32.6Hz, 1H), 7.99 (s, 1H), 7.60 (d, J=6.5Hz, 1H), 3.37 (s, 1H), 1.39 (s, 11H).
4-(N-methyl-N-(thiazol-2-yl) sulfamyl) phenylformic acid
Step 1:
To 4-chlorosulfonyl methyl benzoate (4g; N-methylthiazol-2-amine (1.95g is added in 17.05mmol); 17.05mmol), 1; 2-ethylene dichloride (20mL) and triethylamine (2.38mL; 17.05mmol); and at 100 DEG C, in pressurized vessel on heat block reacting by heating thing 20.5 hours. Vapourisation under reduced pressure solvent. Crude compound is dissolved in methylene dichloride and filters. By silica gel chromatography, utilize the gradient-purified filtrate of the 0-30% ethyl acetate in methylene dichloride, obtain 4-[methyl (thiazol-2-yl) sulfamyl] methyl benzoate (4.22g, 79.2%). 1HNMR (400MHz, DMSO) �� 8.16 (d, J=8.5Hz, 2H), 7.95 (d, J=8.5Hz, 2H), 7.46 (d, J=3.6Hz, 1H), 7.44 (d, J=3.6Hz, 1H), 3.89 (s, 3H), (3.39 s, 3H) .ESI-MSm/z theoretical value: 312.0, measured value: 313.3 (M+1)+; Retention time: 1.52 minutes (running 3 minutes).
Step 2:
To 4-[methyl (thiazol-2-yl) sulfamyl] methyl benzoate (4.22g; 13.5mmol) He in 1,4-bis-alkane (32mL) add saturated NaOH (62mL, 2.5M; 155mmol), and at 50 DEG C, be uniformly mixed thing 1 hour. Reaction mixture is cooled to room temperature. Add ethyl acetate (135mL), it is acidified to pH1 with HCl (37%) afterwards. Separation organic layer and water layer. By ethyl acetate (1 �� 50mL) aqueous layer extracted. Through dried over sodium sulfate organic layer, filtering with under reduced pressure solvent is evaporation, obtains 4-[methyl (thiazol-2-yl) sulfamyl] phenylformic acid (3.63g, 87%) in white solid. ESI-MSm/z theoretical value: 298.0, measured value: 299.1 (M+1)+; Retention time: 1.31 minutes (running 3 minutes).1HNMR (400MHz, DMSO) �� 13.56 (s, 1H), 8.14 (d, J=8.6Hz, 2H), 7.92 (d, J=8.5Hz, 2H), 7.46 (d, J=3.6Hz, 1H), 7.44 (d, J=3.6Hz, 1H), 3.39 (s, 3H).
4-(the fluoro-2-methyl propoxy-of 2-)-3-methoxybenzoic acid
Step 1:
To 4-(2-hydroxy-2-methyl-propoxy-)-3-methoxyl methyl benzoate (509mg at 0 DEG C, 2.00mmol) in the solution in DCM (5mL) drip add 2-methoxyl group-N-(2-methoxy ethyl)-N-(sulfonium triflate alkyl) ethamine (406 �� L, 2.20mmol). At 0 DEG C, stir this mixture 1 hour, remove cooling bath afterwards, and be at room temperature uniformly mixed thing 1 hour. Mixture is poured in water, and extracts with EtOAc (3x). Merge organism, with water, salt water washing, dry (Na2SO4) and steam dry. By column chromatography (0-20%EtOAc in hexane) purifying resistates, obtain 4-(the fluoro-2-methyl-propoxy-of 2-)-3-methoxyl methyl benzoate (450mg, 70%). ESI-MSm/z theoretical value: 256.1, measured value: 257.1 (M+1)+; Retention time: 1.57 minutes (running 3 minutes).
Step 2:
To 4-(the fluoro-2-methyl-propoxy-of 2-)-3-methoxyl methyl benzoate (450mg, 1.76mmol) solution in MeOH (3.6mL) and water (900 �� L) adds NaOH (210mg, 5.27mmol), and at 40 DEG C, be uniformly mixed thing 1 hour. Evaporation MeOH, and the pH to 3 of solution is regulated with 1NHCl. Filtering precipitate, washes with water and drying, obtains 4-(the fluoro-2-methyl propoxy-of 2-)-3-methoxybenzoic acid. ESI-MSm/z theoretical value: 242.2, measured value: 243.7 (M+1)+; Retention time: 1.25 minutes (running 3 minutes).
3-methoxyl group-4-((2,2,2-trifluoro ethoxy) methyl) phenylformic acid
In the 2,2,2 tfifluoroethyl alcohol solution (874 �� L, 12.0mmol) at 0 DEG C, add NaH (60%, 520mg, 13.0mmol), and it is uniformly mixed thing at such a temperature 10 minutes, then at room temperature stir 10 minutes. Mixture is cooled to 0 DEG C, adds 4-(bromotrifluoromethane)-3-methoxyl methyl benzoate (2.59g, 10.0mmol) afterwards. Remove cooling bath, and at room temperature it is uniformly mixed thing 3 hours. This mixture is poured in water, and extracts with EtOAc (3x). Merge organism, with water, salt water washing, dry (MgSO4) and steam dry. The NaOH of crushing is joined in resistates, then adds water (4mL) and MeOH (20mL). At room temperature, thing it is uniformly mixed 1 hour. Evaporation MeOH, and by residual collection in 1NNaOH (30ml), and with dense HCl by pH regulator to pH2. Filtering precipitate, with water (2x) washing, then with hexane (2x) washing and drying, obtains 3-methoxyl group-4-((2,2,2-trifluoro ethoxy) methyl) phenylformic acid.1HNMR (400MHz, CDCl3) �� 7.79 (dd, J=7.8,1.4Hz, 1H), 7.61 (d, J=1.4Hz, 1H), 7.53 (d, J=7.8Hz, 1H), 4.80 (s, 2H), 4.00-3.91 (m, 5H).
Aforesaid method is used to synthesize following compound:
3-methoxyl group-4-((3,3,3-trifluoropropyl oxygen base) methyl) methyl benzoate.
4-(1-hydroxy-2-methyl third-2-base)-3-methoxybenzoic acid
Step 1:
The mixing bromo-3-methoxyl group-phenylformic acid (1.50g, 6.49mmol) of 4-, K2CO3(2.69g, 19.5mmol) and DMF (10mL), and make mixture stir 10 minutes. Drip and add brooethyl benzene (849mL, 7.14mmol), and at room temperature make this mixture stir 1 hour. With salt solution cancellation reaction mixture, and extract with EtOAc (3x). Through dried over sodium sulfate organic layer, filter and concentrate. Use silica gel chromatography (in hexane the EtOAc of 5%-70%) purifying resistates, obtain 4-bromo-3-methoxybenzoic acid benzyl ester (91%). ESI-MSm/z theoretical value: 320.0, measured value: 321.0/323.0 (M+I)+. Retention time: 3.24 minutes (running 4 minutes).
Step 2:
To with the flask of nitrogen purge adds Pd (tBu3P)2(26mg, 0.050mmol), ZnF2(52mg, 0.50mmol) and DMF (4mL). Make reaction mixture stir 10 minutes, add the bromo-3-methoxyl group-peruscabin (323mg, 1.01mmol) of 4-afterwards, then add (2-methyl-prop-1-alkene oxygen base) silane (277 �� L, 1.51mmol). At 80 DEG C, reacting by heating thing spends the night. With salt solution cancellation crude mixture, and extract 3 times with EtOAc. Through dried over sodium sulfate organic layer, and evaporating solvent, obtain 3-methoxyl group-4-(2-methyl isophthalic acid-oxopropan-2-base) peruscabin. ESI-MSm/z theoretical value: 312.4, measured value: 313.4 (M+1)+; Retention time: 3.27 minutes (running 4 minutes).
Step 3:
Then, successively with MeOH (2mL), NaBH4(190mg, 5.03mmol) processes 3-methoxyl group-4-(2-methyl isophthalic acid-oxo third-2-base) peruscabin (thick material, from step 2). Stirred reaction mixture 1 hour, uses salt solution cancellation afterwards, and extracts with EtOAc. Mixing organic layer, through dried over sodium sulfate and evaporate, obtain 4-(1-hydroxy-2-methyl third-2-base)-3-methoxybenzoic acid benzyl ester.
Step 4:
In thick 4-(1-hydroxy-2-methyl third-2-base)-3-methoxybenzoic acid benzyl ester (from step 3), add THF (2mL), then add the NaOH aqueous solution (1.7mL, 3.0M, 5.0mmol). Stirred reaction mixture 3 hours. Reaction mixture is acidified to pH3, and extracts 3 times with EtOAc. Through dried over sodium sulfate organic layer, and evaporating solvent, obtain 4-(1-hydroxy-2-methyl third-2-base)-3-methoxybenzoic acid. ESI-MSm/z theoretical value: 224.1, measured value: 224.2 (M+1)+; Retention time: 2.46 minutes (running 4 minutes).
The fluoro-4-of 3-(2-hydroxy-2-methyl propyl group) phenylformic acid
Step 1:
At room temperature, under nitrogen atmosphere, by diazo methyl-trimethyl-silane (11.6mL, 2.0M, 23.2mmol) drop in the solution of 2-(the fluoro-phenyl of the bromo-2-of 4-) acetic acid (4.50g, 19.3mmol) in toluene (7.7mL) and MeOH (7.7mL). After adding diazomethane and completing, keep lasting yellow. Then, with several acetic acid cancellation reactants, and under reduced pressure except desolventizing. Use 0-10%EtOAc purifying resistates in hexane by silica gel flash column chromatography, obtain 2-(the fluoro-phenyl of the bromo-2-of 4-) methyl acetate (4.32g, 91%).1HNMR (400MHz, CDCl3) �� 7.28-7.22 (m, 2H), 7.15 (t, J=8.0Hz, 1H), 3.71 (s, 3H), 3.63 (d, J=1.0Hz, 2H).
Step 2:
Under nitrogen atmosphere, in ice-water bath, 2-(the 4-bromo-2-fluoro-phenyl) methyl acetate (4.00g of cooling in THF (56mL), 16.2mmol), then dripped through 30 minutes and add bromo-methyl-magnesium (16.2mL, 3M, 48.6mmol). Under ice-water bath cools, continue stirred reaction mixture 2 hours. Then, with saturated aqueous ammonium chloride solution cancellation reaction mixture, and dilute with EtOAc. It is separated each layer, and uses EtOAc aqueous layer extracted. Through Na2SO4The dry organism merged, filters and under reduced pressure concentrates. By silica gel flash column chromatography, it may also be useful to 0-15%EtOAc purifying resistates in hexane, obtain transparent colorless oil 1-(the fluoro-phenyl of the bromo-2-of 4-)-2-methyl-propyl-2-alcohol (3.0g, 75%). ESI-MSm/z theoretical value: 246.0, measured value: 231.1 (M+1)+; Retention time: 1.53 minutes (running 3 minutes). The m/z that LC/MS observes does not have show ontology quality, but-17 fragments.1HNMR (400MHz, CDCl3) �� 7.26-7.21 (m, 2H), 7.14 (t, J=8.1Hz, 1H), 2.78 (d, J=1.4Hz, 2H), 1.24 (d, J=0.8Hz, 6H).
Step 3:
With MeOH (20.0mL, 495mmol) process 1-(the fluoro-phenyl of the bromo-2-of the 4-)-2-methyl-propyl-2-alcohol (2.35g in DMF (26mL), 9.51mmol), diacetyl oxygen base palladium (214mg, 0.951mmol), 3-diphenylphosphino propyl group phenylbenzene phosphine (404mg, 0.951mmol) and Et3N (4.24mL, 30.4mmol). With CO (266mg, 9.51mmol) by vessel filling to 50psi, then it is vented. Repeat this operation twice. Reactant is loaded to 50psi, and heats 15 hours at 80 DEG C. Reaction mixture is cooled, is vented and is distributed between EtOAc/ salt solution. It is separated each layer, and uses EtOAc aqueous layer extracted. The organics washed with brine twice that will merge, through Na2SO4Drying, filters and is condensed into orange. By silica gel flash column chromatography, it may also be useful to 0-30%EtOAc purifying resistates in hexane, obtain the fluoro-4-of 3-(2-hydroxy-2-methyl-propyl group) methyl benzoate (1.83g, 85%). ESI-MSm/z theoretical value: 226.1, measured value: 227.5 (M+1)+; Retention time: 1.29 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.78 (dd, J=7.9,1.7Hz, 1H), 7.71 (dd, J=10.3,1.6Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 3.92 (s, 3H), 2.88 (d, J=1.3Hz, 2H), 1.26 (s, 6H).
Step 4:
By fluoro-for 3-4-(2-hydroxy-2-methyl-propyl group) methyl benzoate (1.59g, 7.03mmol) it is dissolved in THF (40mL), water (200mL) and MeOH (21mL), add LiOH (1.01g, 42.2mmol) afterwards. At 55 DEG C, reacting by heating mixture 30 minutes. Reaction mixture is cooled to room temperature, and under reduced pressure except desolventizing. Resistates is dissolved in water, cools in ice-water bath, and process to pH3 with HCl1M. The throw out obtained by collected by vacuum filtration, is washed with water, and dry under a high vacuum, obtains the fluoro-4-of 3-(2-hydroxy-2-methyl-propyl group) phenylformic acid (999mg, 67%) in white solid. ESI-MSm/z theoretical value: 212.1, measured value: 211.1 (M+1)+; Retention time: 0.98 minute (running 3 minutes, it may also be useful to negative electricity scans from mode).1HNMR (400MHz, CDCl3) �� 7.84 (dd, J=7.9,1.6Hz, 1H), 7.77 (dd, J=10.1,1.6Hz, 1H), 7.39 (d, J=15.1Hz, 1H), 2.91 (s, 2H), 1.28 (s, 6H).
The fluoro-4-of 3-(3-methoxy propyl-1-alkynes base) phenylformic acid
Step 1:
Under argon gas, to the fluoro-methyl benzoate (2.50g, 10.7mmol) of the bromo-3-of the 4-in flask, cupric iodide (I) (204mg, 1.07mmol) and Pd (PPh3)2Cl2(753mg, 1.07mmol) adds DMF (degassed 30 minutes), and reactant is cooled to 0 DEG C. Add Et3N (1.95mL, 14.0mmol), then adds 3-methoxy propyl-1-alkynes (997 �� L, 11.8mmol), and makes mixture stir 70 minutes at 60 DEG C. Mixture is cooled, with diluted ethyl acetate and filtration. In turn with 1MHCl, 10%NH4OH and aqueous salt solu-tion filtrate. Separation organic layer, dry and use ethylacetate-hexane to purify with silica gel, obtain the fluoro-4-of 3-(3-methoxy propyl-1-alkynes base) methyl benzoate. ESI-MSm/z theoretical value: 222.2, measured value: 223.2 (M+1)+; Retention time: 1.53 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.75 (ddd, J=11.2,8.8,1.5Hz, 2H), 7.50 (dd, J=7.9,7.0Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H).
Step 2:
At room temperature, in the fluoro-4-of the 3-in the 2:1THF:MeOH of 15ml (3-methoxy propyl-1-alkynes base) methyl benzoate (1.40g, 6.30mmol), NaOH (1.89mL, 4M, 7.56mmol) is added. At room temperature, stir this mixture 1 hour, remove volatile solvent afterwards. Part is remained by extracted with diethyl ether. Use 1MHCl Acidified aqueous layer, and extract with ether (3x). The ethereal extract that drying merges also concentrates, and obtains the fluoro-4-of 3-(3-methoxy propyl-1-alkynes base) phenylformic acid in white solid. ESI-MSm/z theoretical value: 208.2, measured value: 209.2 (M+1)+; Retention time: 1.22 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.85 (dd, J=8.0,1.4Hz, 1H), 7.80 (dd, J=9.5,1.3Hz, 1H), 7.59-7.49 (m, 1H), 4.39 (s, 2H), 3.48 (s, 3H).
4-(two (2,2,2-trifluoro ethoxy) methyl)-3-chloro-benzoic acid
Under reflux, to the chloro-4-methyl-methyl benzoate (2.00g, 10.8mmol) of 3-and NBS (2.05g, 11.5mmol) at CCl4(9mL) solution in adds AIBN (178mg, 1.08mmol). By this mixture reflux 16 hours, add other AIBN (178mg, 1.08mmol) afterwards. This mixture of reflux 72 hours, is cooled afterwards. Mixture is concentrated to dry, resistates is distributed in Et2Between O and water, it is separated each layer, and uses Et2O (2x) aqueous layer extracted. Organism is merged, with water, salt water washing, dry (MgSO4), and concentrate to dry. By column chromatography (in hexane 0-30%EtOAc) purifying resistates, obtain the chloro-4-of 3-(two brooethyls) methyl benzoate. ESI-MSm/z theoretical value: 342.5, measured value: 342.9 (M+1)+; Retention time: 1.96 minutes (running 3 minutes).
Step 2:
NaH (64mg, 1.6mmol) is added in the solution of 2,2,2 tfifluoroethyl alcohol (109mL, 1.50mmol) in DMF (2.63mL). At room temperature stir this mixture 1 hour, add the chloro-4-of 3-(two brooethyls) methyl benzoate (342mg, 1.00mol) afterwards. At room temperature, stir this mixture 2 hours, it is poured in water afterwards, and extract with EtOAc (3x). Merge organism, with water, salt water washing, dry (Na2SO4) and steam dry. By collecting material in MeOH, add powder shape NaOH (160mg, 4.00mol), and at room temperature stir this mixture 1 hour. Evaporating mixture, and with 1NHCl process (until solution is strongly-acid). Wash precipitated product with water and drying, obtain 4-(two (2,2,2-trifluoro ethoxy) methyl)-3-chloro-benzoic acid. ESI-MSm/z theoretical value: 394.4, measured value: 394.5 (M+1)+; Retention time: 1.74 minutes (running 3 minutes).
4-(1-hydroxyl-2-(2,2,2-trifluoro ethoxy) ethyl) phenylformic acid and 4-(2-hydroxyl-1-(2,2,2-trifluoro ethoxy) ethyl) phenylformic acid
Step 1:
Drip in the solution of 4-acetylbenzoic acid methyl esters (8.91g, 50.0mmol) in AcOH (80mL) and add Br2(2.71mL, 52.5mmol). At room temperature, this mixture is stirred 2 hours. Mixture is cooled to 0 DEG C, and crosses filter solid. With the MeOH solution washing throw out of 1:1, and dry, obtain 4-(2-acetyl bromide) methyl benzoate (10.6g, 82%) in tawny solid.1HNMR (400MHz, CDCl3) �� 8.19-8.12 (m, 2H), 8.04 (d, J=8.5Hz, 2H), 4.47 (s, 2H), 3.96 (s, 3H).
Step 2:
At 0 DEG C, in the stirred solution of 4-(2-acetyl bromide) methyl benzoate (0.59g, 2.3mmol) in MeOH (6mL), add NaBH by part4(92mg, 2.4mmol). Remove cooling bath, and at room temperature stir this mixture 1 hour. Add K2CO3(317mg, 2.30mmol), and at room temperature stir this mixture 72 hours. Mixture is poured in water, and uses Et2O (3x) extracts. Merge organism, with water, salt water washing, dry (MgSO4) and steam dry, obtaining is 4-(oxyethane-2-base) methyl benzoate (370mg, 90%) of white solid. ESI-MSm/z theoretical value: 178.2, measured value: 179.1 (M+1)+; Retention time: 1.14 minutes (running 3 minutes).
Step 3:
NaH (10mg, 0.24mmol) is added in 2,2,2 tfifluoroethyl alcohol (0.50mL, 6.9mmol). It is uniformly mixed thing 5 minutes, adds 4-(oxyethane-2-base) methyl benzoate (36mg, 0.20mmol) afterwards, and heat 2 hours at 70 DEG C. Add the NaOH (40mg, 1.0mmol) of crushing, then add water (0.1mL), and at 40 DEG C, be uniformly mixed thing 3 hours. Evaporating mixture, and resistates is distributed between 1NHCl and EtOAc. It is separated each layer, and by EtOAc (2x) aqueous layer extracted. Merging organism and steam dry, obtaining is the 4-[1-hydroxyl-2-(2,2 of oily matter, 2-trifluoro ethoxy) ethyl] phenylformic acid and 4-(2-hydroxyl-1-(2,2,2-trifluoro ethoxy) ethyl) mixture of phenylformic acid (30mg, 57%). ESI-MSm/z theoretical value: 264.1, measured value: 265.1 (M+1)+; Retention time: 1.07 minutes (running 3 minutes).
(4-isopropoxy-3-p-methoxy-phenyl) (2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1-base) first ketone
At room temperature, make 2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine] dihydrochloride (69mg, 0.20mmol), 4-isopropoxy-3-methoxybenzoic acid (42mg, 0.20mmol), HATU (76mg, 0.20mmol), Et3N (112 �� L, 0.80mmol) and the mixture of DMF (2mL) stir 3 hours. Filter this mixture, and by anti-phase preparation HPLC (10-99%ACN/ water) purifying. The concentrated fraction expected, obtain (the 4-isopropoxy-3-p-methoxy-phenyl) in amorphous white solid (2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1-base) first ketone. ESI-MSm/z theoretical value: 465.2, measured value: 466.3 (M+1)+; Retention time 1.23 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.01 (d, J=1.7Hz, 1H), 6.97 (dd, J=8.2, 1.7Hz, 1H), 6.88 (d, J=8.3Hz, 1H), 6.53 (d, J=3.0Hz, 1H), 5.94 (d, J=3.5Hz, 1H), 4.57 (dt, J=12.2, 6.1Hz, 1H), 4.52 (s, 1H), 3.99 (s, 2H), 3.87 (s, 3H), 3.69 (s, 1H), 3.40 (s, 1H), 3.34 (t, J=5.4Hz, 3H), 2.39 (s, 3H), 2.11 (s, 2H), 1.82 (s, 2H), 1.38 (d, J=6.1Hz, 6H).
(4-isopropoxy-3-p-methoxy-phenyl) (6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1-base) first ketone
At ambient temperature, to 6-(trifluoromethyl) spiral shell [3,4-dihydro-2 h-pyrrole also [1,2-a] pyrazine-1,4 '-piperidines] dihydrochloride (475mg, 1.43mmol), 4-isopropoxy-3-methoxyl group-phenylformic acid (361mg, 1.72mmol) and 1-1-Hydroxy Benzotriazole (232mg, 1.72mmol) are at CH2Cl2(5.5mL) stirred solution in adds 3-(ethylimino methene amido)-N, N-dimethyl-propyl-1-amine (266mg, 1.72mmol), then 4-methylmorpholine (786 �� L, 7.15mmol). At room temperature, thing it is uniformly mixed 16 hours. This mixture is poured in water, and extracts with EtOAc (3x). Merge organism, with 0.1NHCl, 1NNaOH, water, salt water washing, dry (Na2SO4) and steam dry. By column chromatography (0-100% ethyl acetate/hexane) purifying resistates, obtain (4-isopropoxy-3-methoxyl group-phenyl)-[6-(trifluoromethyl) spiral shell [3,4-dihydro-2 h-pyrrole also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-Ji] first ketone (623mg, 96%). ESI-MSm/z theoretical value: 451.2, measured value: 452.3 (M+1)+; Retention time: 1.30 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.03 (d, J=1.9Hz, 1H), 6.98 (dd, J=8.2,1.9Hz, 1H), 6.88 (d, J=8.3Hz, 1H), 6.54 (d, J=3.7Hz, 1H), 5.93 (d, J=3.8Hz, 1H), (4.56 dd, J=12.2,6.1Hz, 1H), 4.52 (s, 1H), 3.94 (s, 2H), 3.88 (s, 3H), 3.69 (s, 1H), 3.47 (s, 2H), 3.27 (s, 2H), 1.87 (s, 4H), (1.38 d, J=6.1Hz, 6H).
Aforesaid method is used to prepare following compound:
1-(1-(4-isopropoxy-3-anisoyl)-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-2 '-Ji) second ketone
At room temperature, by Acetyl Chloride 98Min. (158 �� L, 2.22mmol) it is added drop-wise to (4-isopropoxy-3-methoxyl group-phenyl)-[6-(trifluoromethyl) spiral shell [3,4-dihydro-2 h-pyrrole also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-Ji] first ketone (100mg, 0.222mmol) and pyridine (1ml) mixture in. At room temperature, make this mixture stir 16 hours, it is distributed between ethyl acetate and 1NHCl afterwards. It is separated each layer, and with 1NHCl, water washing organic layer, uses salt water washing afterwards. Through dried over sodium sulfate organic layer, and under reduced pressure concentrate. Resistates is placed in DMF; and by preparation-HPLC (the ACN/ water of 10-99% containing ammonium formiate modifier) purifying; obtain 1-[1 '-(4-isopropoxy-3-methoxyl group-benzoyl)-6-(trifluoromethyl) spiral shell [3 in white solid; 4-pyrrolin also [1; 2-a] pyrazine-1; 4 '-piperidines]-2-base] second ketone (60mg, 53%). ESI-MSm/z theoretical value: 493.2, measured value: 494.7 (M+1)+; Retention time: 1.70 minutes (running 3 minutes).1HNMR (400MHz, CDCl3) �� 7.06 (d, J=1.8Hz, 1H), 7.05-6.98 (m, 1H), 6.88 (d, J=8.2Hz, 1H), 6.55 (d, J=3.3Hz, 1H), 6.15 (d, J=3.9Hz, 1H), 4.57 (d, J=6.1Hz, 1H), 4.19-4.10 (m, 2H), 3.88 (m, s, 5H), 3.79 (s, 2H), (3.70-3.52 m, J=31.5Hz, 2H), 3.11 (s, 2H), 2.24 (s, 3H), 1.92-1.75 (m, 2H), (1.38 d, J=6.1Hz, 6H).
Aforesaid method is used to synthesize following compound: 1-(4-isopropoxy-3-anisoyl)-6 '-(trifluoromethyl)-3 '; 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4; 1 '-pyrrolo-[1; 2-a] pyrazine]-2 '-carboxylate methyl ester and 1-(4-isopropoxy-3-anisoyl)-6 '-(trifluoromethyl)-3 '; 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4; 1 '-pyrrolo-[1,2-a] pyrazine]-2 '-carboxylic acid, ethyl ester.
The fluoro-1-of 2,2,2-tri-[1 '-[4-(2-methoxyl group-3-pyridyl)-3-methyl-benzoyl]-2-methyl-spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone
To having Pd (dppf) Cl2(5.5mg; 2-methoxypyridine-3-ylboronic acid (0.10mmol) being added in NMP (0.2mL) in microtubule 0.075mmol); then add 1-(1-(4-bromine 3-methyl benzoyl)-2 '-methyl-3 '; 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4; 1 '-pyrrolo-[1; 2-a] pyrazine]-6 '-Ji) solution of-2,2,2-trifluoroethanone (0.75mmol) in DMF (0.3mL) and Na2CO3The aqueous solution (2M, 4mmol). At 80 DEG C, jolting reaction mixture 16 hours. Filter; then with the use of preparation-HPLC (the ACN aqueous solution (HCl modifier) of 1-99%) purifying; obtain 2; 2; the fluoro-1-of 2-tri-[1 '-[4-(2-methoxyl group-3-pyridyl)-3-methyl-benzoyl]-2-methyl-spiral shell [3; 4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone. ESI-MSm/z theoretical value: 526.2, measured value: 527.3 (M+1)+; Retention time: 1.38 minutes (running 3 minutes).
Aforesaid method is used to synthesize following compound:
5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl base) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carbonyl] phenyl] pyridine-2-first nitrile,
1-[1 '-[4-(1-ethyl imidazol(e)-4-base)-3-methyl-benzoyl]-2-methyl-spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base]-2,2,2-trifluoro-ethanone,
The fluoro-1-of 2,2,2-tri-[2-methyl isophthalic acid '-[3-methyl-4-(2-methyl-4-pyridyl) benzoyl] spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone,
The fluoro-1-of 2,2,2-tri-[2-methyl isophthalic acid '-[3-methyl-4-(1-methylpyrazole-3-base) benzoyl] spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone,
The fluoro-1-of 2,2,2-tri-[2-methyl isophthalic acid '-[3-methyl-4-(1-methyl-pyrazol-4-yl) benzoyl] spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone,
The fluoro-1-of 2,2,2-tri-[1 '-[4-(4-p-methoxy-phenyl)-3-methyl-benzoyl]-2-methyl-spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone,
1-[1 '-[4-(3-chloro-phenyl-)-3-methyl-benzoyl]-2-methyl-spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base]-2,2,2-trifluoro-ethanone,
The fluoro-1-of 2,2,2-tri-[2-methyl isophthalic acid '-[3-methyl-4-(2-methylpyrazole-3-base) benzoyl] spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone,
N-[5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl base) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-1 '-carbonyl] phenyl]-2-pyridyl] ethanamide,
1-[1 '-[4-[2-(di methylamino) pyrimidine-5-base]-3-methyl-benzoyl]-2-methyl-spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base]-2,2,2-trifluoro-ethanone,
The fluoro-1-of 2,2,2-tri-[2-methyl isophthalic acid '-[3-methyl-4-[3-(trifluoromethyl)-1H-pyrazoles-4-base] benzoyl] spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone, and
The fluoro-1-of 2,2,2-tri-[2-methyl isophthalic acid '-(3-methyl-4-pyrimidine-5-base-benzoyl) spiral shell [3,4-pyrrolin is [1,2-a] pyrazine-1,4 '-piperidines also]-6-base] second ketone.
(2-(3-hydroxyl pyrrolidine-1-base) pyridin-3-yl) (2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1-base) first ketone
At 80 DEG C, stir (the chloro-3-pyridyl of 2-)-[2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-Ji] mixture in DMF (0.5mL) of first ketone (0.1mol) and tetramethyleneimine-3-alcohol (0.3mmol) 16 hours. Add other tetramethyleneimine-3-alcohol (0.5mmol), and at 150 DEG C, stir this mixture 16 hours. Filter this mixture, and it is prepared type-HPLC (the ACN aqueous solution of 10-90%), obtain (2-(3-hydroxyl pyrrolidine-1-base) pyridin-3-yl) (2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1-base) first ketone. ESI-MSm/z theoretical value: 463.5, measured value: 464.3 (M+1)+; Retention time: 0.75 minute (running 3 minutes).
Aforesaid method is used to synthesize following compound:
(2-(3-fluoropyrrolidine-1-base) pyridin-3-yl) (2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1-base) first ketone and (2-(3,3-bis-fluoropyrrolidine-1-base) pyridin-3-yl) (2 '-methyl-6 '-(trifluoromethyl)-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4,1 '-pyrrolo-[1,2-a] pyrazine]-1-base) first ketone.
2; the fluoro-1-of 2,2-tri-(1-(3-methoxyl group-4-(the third-1-alkene-2-base oxygen base) benzoyl)-2 '-methyl-3 ', 4 '-two hydrogen-2 ' H-spiral shell [piperidines-4; 1 '-pyrrolo-[1,2-a] pyrazine]-6 '-Ji) second ketone
Step 1:
At room temperature, by 4-methylmorpholine (1.59mL, 14.4mmol) join 2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines] dihydrochloride (1.00g, 2.89mmol), 4-hydroxyl-3-methoxyl group-phenylformic acid (486mg, 2.89mmol), EDCI (831mg, 4.33mmol), in the mixture of HOBt (585mg, 4.33mmol) and DMF (10mL). At 60 DEG C, heat this mixture overnight, it is cooled to room temperature afterwards, and is distributed between ethyl acetate and 1NHCl. It is separated each layer, and by ethyl acetate (3x) aqueous layer extracted. The organic layer washed with brine that will merge, through dried over sodium sulfate, filters and concentrates. Resistates is made to carry out column chromatography (0-100% ethyl acetate/hexane), obtain (4-hydroxyl-3-methoxyl group-phenyl)-[2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-Ji] first ketone (690mg, 58%). ESI-MSm/z theoretical value: 423.2, measured value: 424.1 (M+1)+; Retention time: 1.16 minutes (running 3 minutes).1HNMR (400MHz, CD3CN) �� 7.04 (d, J=1.8Hz, 1H), 6.94 (dd, J=8.1, 1.9Hz, 1H), 6.87 (d, J=8.1Hz, 1H), 6.82 (s, 1H), 6.62-6.56 (m, 1H), 6.05 (d, J=3.9Hz, 1H), 4.35 (s, 1H), 4.00 (t, J=6.0Hz, 2H), 3.89 (s, 3H), 3.64 (s, 2H), 3.36 (t, J=6.0Hz, 2H), 3.29 (s, 1H), 2.36 (s, 3H), 2.16-2.04 (m, 2H), 1.81 (dd, J=17.1, 7.3Hz, 2H) .26-7.21 (m, 2H), 7.14 (t, J=8.1Hz, 1H), 2.78 (d, J=1.4Hz, 2H), 1.24 (d, J=0.8Hz, 6H).
Step 2:
At room temperature, Cs in bottle is stirred2CO3(115mg, 0.354mmol), methyl ethyl diketone (12 �� L, 0.12mmol), CuCl (5.8mg, 0.059mmol) and the mixture 5 minutes of THF (2.5mL), add (4-hydroxyl-3-methoxyl group-phenyl)-[2-methyl-6-(trifluoromethyl) spiral shell [3 afterwards, 4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-Ji] first ketone (100mg, 0.236mmol), then 2-bromine third-1-alkene (27 �� L, 0.31mmol) is added. Lid is added and heated overnight at 70 DEG C to bottle. Mixture is cooled to room temperature, filters and under reduced pressure concentrate. Resistates is made to carry out column chromatography (ethyl acetate/hexane of 0-100%), obtain (4-pseudoallyl oxygen base-3-methoxyl group-phenyl)-[2-methyl-6-(trifluoromethyl) spiral shell [3,4-pyrrolin also [1,2-a] pyrazine-1,4 '-piperidines]-1 '-Ji] first ketone (8.9mg, 8%) .ESI-MSm/z theoretical value: 463.2, measured value: 464.3 (M+1)+; Retention time: 1.47 minutes (running 3 minutes).1HNMR (400MHz, CD3CN) �� 7.12 (d, J=1.8Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 7.01 (dd, J=8.0, 1.8Hz, 1H), 6.60 (d, J=3.4Hz, 1H), 6.07 (d, J=3.7Hz, 1H), 4.42 (s, 1H), 4.12 (dd, J=1.6, 0.9Hz, 1H), 4.01 (t, J=6.0Hz, 2H), 3.85 (s, 3H), 3.79 (d, J=1.7Hz, 1H), 3.67-3.40 (m, 2H), 3.36 (t, J=5.6Hz, 2H), 3.20 (s, 1H), 2.36 (s, 3H), 2.18 (s, 2H), 2.00 (d, J=0.7Hz, 3H), 1.83 (s, 2H).
Following table 2 lists the analytical data of table 1 compound.
Table 2.
The assay method of character is suppressed for detecting and measure the NaV of compound
Use the E-VIPR blooming potentiometry of electricity irritation
Sodium channel is the voltage-dependent protein that can bring out membrane voltage change activation by applying electric field. Apparatus of electro-stimulation and using method thereof describe and are being incorporated to herein in IonChannelAssayMethodsPCT/US01/21652 as a reference, and are called E-VIPR. This instrument comprises microtitration sheet processor, for the amplifier that excites coumarine dye records tonka bean camphor and oxygen alcohol class (oxonol) is launched optical system, waveform generator, electric current or voltage control and the device inserted in the hole by electrode simultaneously. Under conformity calculation machine controls, the cell that the electrical stimulation scheme of user-sequencing is sent in the hole of microtiter plate by this instrument.
On E-VIPR measure before 24 hours, the HEK cell expressing people's NaV hypotype (such as NaV1.7) is seeded on the 384-orifice plate scribbling polylysine with 15,000-20,000 cells/well. The clone expressing NaV interested carries out other hypotype with parallel pattern. Make HEK cell be supplemented with 10%FBS (foetal calf serum, qualified; And 1%Pen-Strep (Pen .-Strep GibcoBRL#_16140-071); GibcoBRL#_15140-122) growth in substratum (accurately composition is specific for each cell type and NaV hypotype). Cell is added in lid flask, at 90% humidity and 10%CO what ventilate2Under grow to 100% fusion. Usually divided by tryptic digestion 1:10 or 1:20, depend on time-histories needs, and grow 2-3 days, again divide afterwards.
Reagent and solution:
100mg/mL general stream Buddhist nun gram (Pluronic) F-127 (Sigma#P2443), in anhydrous DMSO
Compound plate: 384-hole circle base plate, such as Corning384-hole polypropylene round bottom #3656
Cell plate: 384-hole tissue culture treated plate, such as Greiner#781091-1B
10mMDiSBAC6(3) (Aurora#00-100-010), in anhydrous DMSO
10mMCC2-DMPE (Aurora#00-100-008), in anhydrous DMSO
200mMABSC1, at H2In 0
Bath1 damping fluid. Glucose 10mM (1.8g/L), magnesium chloride (anhydrous) 1mM (0.095g/L), calcium chloride 2mM (0.222g/L), HEPES10mM (2.38g/L), Repone K 4.5mM (0.335g/L), sodium-chlor 160mM (9.35g/L).
Own radical dye solution: Bath1 damping fluid+0.5% beta-cyclodextrin (is prepared, Sigma#C4767) before use, 8 ��Ms of CC2-DMPE+2.5 ��M of DiSBAC6(3). In order to prepare this solution, add volume and equal CC2-DMPE+DiSBAC6(3) the 10% of volume general stream Buddhist nun gram F127 stores up liquid. Preparation order, for first to mix general stream Buddhist nun gram and CC2-DMPE, then adds DiSBAC6(3) carry out vortex simultaneously, then add Bath1+ beta-cyclodextrin.
Mensuration scheme:
1) compound (in pure DMSO) is put in advance sample in compound plate, vehicle comparison (pure DMSO), positive control (DMSO of 20mM tetracaine stores up liquid, is finally 125 ��Ms in mensuration) and test compound are joined in each hole with final concentration needed for 160x in pure DMSO. Finalization compound plate bulk will be that 80 �� L are (from 80-times of intermediate dilute liquid of 1 �� LDMSO point sample; It is 160-doubly final diluent after transferring to cell plate). In mensuration, the final DMSO concentration in all holes is 0.625%.
2) own radical dye solution is prepared.
3) cell plate are prepared. On mensuration same day, pump out substratum and with the Bath1 solution washing cell three times of 100 �� l, keep each hole 25 �� L residual volume.
4) own radical dye solution by every hole 25 �� L is assigned in cell plate. 20-35 minute is cultivated under room temperature or envrionment conditions.
5) Bath1 by every hole 80 �� L is assigned in compound plate. Add turmeric yellow-17 (1mM), and Repone K can change into 20mM from 4.5, depend on NaV hypotype and measure susceptibility.
6) with the Bath1 washed cell plate three times of every hole 100 �� L, the residual volume of 25 �� L is left. Then, the every hole 25 �� L from compound plate is transferred to cell plate. 20-35 minute is cultivated under room temperature/envrionment conditions.
7) on E-VIPR, plate is read. Using current control amplifier to transmit and stimulate ripple pulse, be generally 9 seconds, scan rate is 400Hz. Carry out pre-stimulation record 0.5 second, to obtain the intensity benchmark not stimulated. Applying stimulus waveform 9 seconds, after then stimulating, record relaxes to stationary state for 0.5 second to check. For each cell type, the stimulus waveform of electricity irritation is specificity, and can change the value, time length and the frequency that apply electric current to provide optimum determining signal.
Data analysis
Analytical data and with in 460nm and 580nm passage measure emissive porwer subtracting background value after normalization method ratio carry out record. Then, from each mensuration passage subtracting background intensity. Background intensity is that the emissive porwer by measuring the mensuration hole from the same process that there is not cell during the identical time obtains. Then, it may also be useful to the ratio report that following formula obtains take time as the reaction of function:
By calculating initial (Ri) and final (Rf) ratio simplifies data further. Average ratio value during these ratios are part or all of pre-stimulation and during stimulation period sampling spot. Then, calculate the reaction R=R stimulatedf/ Ri, and report with the function of time.
Under at the compound (positive control) with required character, such as tetracaine exists, and pharmacological agents (negative control) not in the presence of carry out mensuration to obtain control reaction. As above feminine gender (N) is calculated and reaction that positive (P) compares. Compound antagonistic activity A is defined as:
Wherein R is the ratio reaction of test compounds.
Electrophysiology that is active for NaV and test compounds suppression property measures
Patch clamp electrophysiology is used to evaluate effect in dorsal root ganglion neurons of sodium channel blockers and selectivity. From dorsal root ganglion be separated rat neurone, and maintain NGF (50ng/mL) exist under substratum (substratum is made up of the NeurobasalA being supplemented with B27, glutamine and microbiotic) in 2 to 10 days. Estimate and differentiated minor diameter neurone (nociceptor, diameter is 8-12 ��m), and adopted the tiny tips glass electrode being connected to amplifier (AxonInstruments) to detect. Under cell is remained on-60mV, it may also be useful to the IC50 of " voltage clamp " mode evaluation compound. In addition, " current clamp " pattern test compounds is used to block effect of the action potential because of current injector generation. The result of these experiments contributes to defining the efficacy characteristics of compound.
Ionworks measures
Automatic patch clamp system IonWorks (MolecularDevicesCorporation, Inc.) is used to record sodium current. Collect the cell expressing Nav hypotype from tissue culture and it is placed in suspension with every mLBath150 ten thousand-4 1,000,000 cell. The response applying of IonWorks apparatus measures is similar to tradition patch clamp and measures the voltage clamp of (difference is to use 384-well format) and produce sodium current change. Use IonWorks, by, before and after adding test compounds, making cell from the specific maintenance current potential depolarize of experiment to the test potential of about 0mV, measure dose-response relationship with voltage clamp pattern. Compound is measured on the impact of electric current under test potential.
1-benzo nitrogen -2-ketone combines and measures
The sodium channel of the compounds of this invention suppresses character to pass through at Williams, B.S.etal., " CharacterizationofaNewClassofPotentInhibitorsoftheVoltag e-GatedSodiumChannelNaV1.7, "Biochemistry, the assay method described in 2007,46,14693-14703 is determined, its whole content is incorporated to herein as a reference.
As used measured by above-described mensuration, one or more sodium channels are had activity by the compound of this paper exemplified by table 1, as presented in table 3.
Table 3.
As apparent to those skilled in the art, it is possible to when not deviating from scope, embodiment described herein is carried out many modifications and change. There is provided particular described herein as just citing.

Claims (35)

1. the compound of formula I:
Or its pharmacologically acceptable salt,
Wherein, independent ground when every time occurring:
R1For H, C1-C8 alkyl, C3-C8 cycloalkyl, halogen, CN, NR8SO2R8��SO2R8��SR8��SOR8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3, Heterocyclylalkyl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or two R1It is combined together to form oxo group, or 3 to 7 yuan of fused rings alkyl rings, or the ring of 3 to 7 yuan of volutions;
R2For H, C1-C8 alkyl, halogen, C1-C8 haloalkyl, CN, OH, SO2R8��SR8��SOR8��COR8��CO2R8��CON(R8)2��SO2N(R8)2��CF3��CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute;
R3For H, C1-C8 alkyl, C3-C8 cycloalkyl, CO2R8��COR8��COH��CON(R8)2��CF3��CH2CF3��CH2CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R4For H, C1-C8 alkyl, halogen, C3-C8 cycloalkyl, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or 2 R4It is combined together to form 3 to 7 yuan of cycloalkyl rings of thick conjunction;
R8For H, C1-C8 alkyl, CF3, C3-C8 cycloalkyl, fluoro-alkyl, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR substitutes, or 2 R8The atom being connected with them is combined together to form ring;
R9For H, CF3��CO2R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, Heterocyclylalkyl, N (R)2��NRCOR��CON(R)2, CN, halogen or SO2R;
R is H, C1-C8 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl or Heterocyclylalkyl;
A is
Wherein:
R5For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CHF2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R6For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, C3-C8 ring alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R7For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��OSO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-(R9)p, wherein p is 1 or 2 and wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute; Or
The R of twice appearance5With R6Or R6With R7It is all C1-C8 alkyl, and is formed and comprise 2 heteroatomic rings at the most together with the carbon connected with their;
M is the integer of 0 to 4, comprises end value;
N is the integer of 0 to 3, comprises end value; And
O is the integer of 0 to 4, comprises end value.
2. the compound of claim 1, wherein, independent ground when every time occurring:
R1For H, C1-C6 alkyl, C3-C8 cycloalkyl, halogen, CN, NR8SO2R8��SO2R8��SR8��SOR8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3, Heterocyclylalkyl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or two R1It is combined together to form oxo group, or 3 to 7 yuan of fused rings alkyl rings, or the ring of 3 to 7 yuan of volutions;
R2For H, C1-C6 alkyl, C1-C6 haloalkyl, CN, OH, SO2R8��SR8��SOR8��CO2R8��CON(R8)2��SO2N(R8)2��CF3��CHF2, or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute;
R3For H, C1-C6 alkyl, C3-C8 cycloalkyl, CO2R8��COR8��COH��CON(R8)2��CF3��CH2CF3��CH2CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R4For H, C1-C6 alkyl, halogen, C3-C8 cycloalkyl, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or 2 R4It is combined together to form 3 to 7 yuan of cycloalkyl rings of thick conjunction;
R8For H, C1-C6 alkyl, CF3, C3-C8 cycloalkyl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR substitutes, or 2 R8The atom being connected with them is combined together to form ring;
R9For H, CF3��CO2R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, Heterocyclylalkyl, N (R)2��NRCOR��CON(R)2, CN or SO2R;
R is H, C1-C6 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl or Heterocyclylalkyl;
M is the integer of 0 to 4, comprises end value;
N is the integer of 0 to 3, comprises end value; And
O is the integer of 0 to 4, comprises end value.
3. the compound of claim 1, wherein R1For C1-C8 alkyl or two R1The atom being connected with them is combined together to form the cycloalkyl of 3 to 7 yuan of thick conjunctions or the ring of volution.
4. the compound of claim 1, wherein R1For CH3Or two R1It is combined together to form the cyclohexyl ring of thick conjunction.
5. the compound of claim 1, wherein R2For H, C1-C8 alkyl, halogen, CF3��CN��COR8��CON(R8)2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute.
6. the compound of claim 1, wherein R2For COCF3��COtBu��Cl��COCH3��CF2CF3��CH2CF3��CF3��CN��Br��COCH(CH3)2��COCH2CH3��SO2CH3��COPh��
7. the compound of claim 1, wherein R3For H, C1-C8 alkyl, CO2R8��COR8��COH��CON(R8)2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute.
8. the compound of claim 1, wherein R3For H, CH3��CH2CH3��CH2CH2OCH3��CH2CH2OH��CH2CO2CH2CH3��CH2CON(CH3)2��CH2CONH2��CH2CN, benzyl, cyclobutyl, CH2CH(CH2)2��CH(CH2)2��CH2CF3��CH2CHF2��COCH3��COCH2CH3��CO2CH3��CO2CH2CH3��COH��CON(CH3)2Or CONHCH3��
9. the compound of claim 1, wherein R4For H, halogen or C1-C8 alkyl.
10. the compound of claim 1, wherein R4For H, F or CH3��
The compound of 11. claims 1, wherein m is 0,1 or 2.
The compound of 12. claims 1, wherein n is 0,1 or 2.
The compound of 13. claims 1, wherein o is 0 or 1.
The compound of 14. claims 1, wherein R5For H, C1-C8 alkyl, C1-C8 alkoxyl group, halogen, OCF3��OCHF2��R9Or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR7Substitute.
The compound of 15. claims 1, wherein R5For H, CH3��OCH3��OCF3��OPh��Ph��OCHF2Or F.
The compound of 16. claims 1, wherein R6For H, C1-C8 alkyl, C1-C8 alkoxyl group, halogen, R9Or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute.
The compound of 17. claims 1, wherein R6For H, CH3��OCH3��OCH2CH3��OCH2CH2CH3��OCH(CH3)2��CF3��CN��Ph��SO2CH3��OH��CH(CH3)2��OCH2CH2CH2CH3, F, Cl or CH2OH��
The compound of 18. claims 1, wherein R7For H, C1-C8 alkyl, C1-C8 alkoxyl group, SO2R8��OSO2R8��SO2N(R8)2��R9��OCHF2��OCF3, or straight chain, side chain or ring-type (C1-C8)-(R9)p, wherein p is 1 or 2 and wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute.
The compound of 19. formula I:
Or its pharmacologically acceptable salt,
Wherein, independent ground when every time occurring:
R1For H, C1-C8 alkyl, C3-C8 cycloalkyl, halogen, CN, NR8SO2R8��SO2R8��SR8��SOR8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3, Heterocyclylalkyl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or two R1It is combined together to form oxo group, or 3 to 7 yuan of fused rings alkyl rings, or the ring of 3 to 7 yuan of volutions;
R2For H, C1-C8 alkyl, halogen, C1-C8 haloalkyl, CN, OH, SO2R8��SR8��SOR8��COR8��CO2R8��CON(R8)2��SO2N(R8)2��CF3��CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute;
R3For H, C1-C8 alkyl, C3-C8 cycloalkyl, CO2R8��COR8��COH��CON(R8)2��CF3��CH2CF3��CH2CHF2Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R4For H, C1-C8 alkyl, halogen, C3-C8 cycloalkyl, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute, or 2 R4It is combined together to form 3 to 7 yuan of cycloalkyl rings of thick conjunction;
R8For H, C1-C8 alkyl, CF3, C3-C8 cycloalkyl, fluoro-alkyl, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2Or NR substitutes, or 2 R8The atom being connected with them is combined together to form ring;
R9For H, CF3��CO2R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, Heterocyclylalkyl, N (R)2��NRCOR��CON(R)2, CN, halogen or SO2R;
R is H, C1-C8 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl or Heterocyclylalkyl;
A is
Wherein:
R5For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CHF2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R6For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, C3-C8 ring alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R7For H, CH3��CH2CH3, tBu, Cl, F, OH, C (=CH2)CH3, OC (=CH2)CH3��OCH3��OCH2CH2CH2CH3��CH2OH��OCH2CH2OH��OCH2CH2CH2OH��OtBu��OCH(CH3)(CH2CH3)��OCH2C(CH3)2OH��C(CH3)2OH��CH2C(CH3)2OH��CH(OH)CH(CH3)2��C(CH3)2CH2OH��OCH2CH2CH(CH3)2��OCH2CH2CH3��OCH(CH3)2��OCH2CH2OCH3��SO2CH3��SO2tBu��SO2CH2CH3��SO2CH2CH(CH3)2��SO2CH(CH3)2��SO2NH(CH3)��SO2NH(CH(CH2)2)��SO2NH(CH2CH3)��SO2NH(CH(CH3)2)��SO2N(CH3)2��OPh��Ph��OCH2CH2OCH3��CH(CH3)2��SO2N(CH2CH2CH3)2��CH2CH2CH2CH3��CH2CH2CH3��OCH2CH2CH2CH3��CH2OPh��OCH2Ph��CH2CH2CH2CH2CH3��OCH2CH3��OCH2CH(CH3)2��CH2Ph��CCCH2OCH3��SO2CHF2��OCF3��OCHF2��CH2CH(CH3)2��OCH2tBu��OCH2CF3�� CH2OCH2CH2CF3��CH2OCH2CF3��SO2CF3��C(CH3)2CH2CH3��C(CH2CH3)3��CH(OCH2CF3)2��CF3��OCH2C(CH3)2F�� CH(OH)CH2OCH2CF3��CH(OCH2CF3)CH2OH��OSO2CF3��Or OCH2CH2OCF3;
M is the integer of 0 to 4, comprises end value;
N is the integer of 0 to 3, comprises end value; And
O is the integer of 0 to 4, comprises end value.
The compound of 20. claims 1, whereinFor:
The compound of 21. claims 1, wherein said compound has formula IA:
Wherein
R2For C1-C8 alkyl, halogen, C1-C8 haloalkyl, CN, OH, SO2R8��SR8��SOR8��COR8��CO2R8��CON(R8)2��SO2N(R8)2��CF3��CHF2, or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by O, CO, S, SO, SO2��CF2Or NR8Substitute;
R3For H, C1-C8 alkyl, CO2R8��COR8��COH��CON(R8)2��CF3Or straight chain, side chain or ring-type (C1-C8)-R9, wherein two CH at the most2Unit can by CF2��O��CO��S��SO��SO2Or NR8Substitute;
R6For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, C3-C8 ring alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute;
R7For H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, halogen, CN, OH, OR8��N(R8)2��NR8SO2R8��SO2R8��SOR8��SR8��CO2R8��NR8COR8��NR8CO2R8��CON(R8)2��SO2N(R8)2��CF3��OCF3��OCHF2��R9, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, heteroaryl or straight chain, side chain or ring-type (C1-C8)-R9, wherein three CH at the most2Unit can by O, CO, S, SO, SO2Or NR8Substitute.
The compound of 22. claims 21, wherein R2For H, COCF3��COtBu��Cl��COCH3��CF2CF3��CH2CF3��CF3��CN��Br��COCH(CH3)2��COCH2CH3��CH(OH)CF3��SO2CH3��COPh��
The compound of 23. claims 21, wherein R3For H, CH3��CH2CH3��CH2CH2OCH3��CH2CH2OH��CH2CO2CH2CH3��CH2CON(CH3)2��CH2CONH2��CH2CN, benzyl, cyclobutyl, CH2CH(CH3)2��CH(CH3)2��CH2CF3��CH2CHF2��COCH3��COCH2CH3��CO2CH3��CO2CH2CH3��COH��CONH(CH3)2Or CONHCH3��
The compound of 24. claims 21, wherein R6For H, CH3��OCH3��OCH2CH3��OCH2CH2CH3��OCH(CH3)2��CF3��CN��Ph��SO2CH3��OH��CH(CH3)2��OCH2CH2CH2CH3, F, Cl or CH2OH��
The compound of 25. claims 21, wherein R7For H, CH3��CH2CH3, tBu, Cl, F, OH, C (=CH2)CH3, OC (=CH2)CH3��OCH3��OCH2CH2CH2CH3��CH2OH��OCH2CH2OH��OCH2CH2CH2OH��OtBu��OCH(CH3)(CH2CH3)��OCH2C(CH3)2OH��C(CH3)2OH��CH2C(CH3)2OH��CH(OH)CH(CH3)2��C(CH3)2CH2OH��OCH2CH2CH(CH3)2��OCH2CH2CH3��OCH(CH3)2��OCH2CH2OCH3��SO2CH3��SO2tBu��SO2CH2CH3��SO2CH2CH(CH3)2��SO2CH(CH3)2��SO2NH(CH3)��SO2NH(CH(CH2)2)��SO2NH(CH2CH3)��SO2NH(CH(CH3)2)��SO2N(CH3)2��OPh��Ph��OCH2CH2OCH3��CH(CH3)2��SO2N(CH2CH2CH3)2��CH2CH2CH2CH3��CH2CH2CH3��OCH2CH2CH2CH3��CH2OPh��OCH2Ph��CH2CH2CH2CH2CH3��OCH2CH3��OCH2CH(CH3)2��CH2Ph��CCCH2OCH3��SO2CHF2��OCF3��OCHF2��CH2CH(CH3)2��OCH2tBu��OCH2CF3�� CH2OCH2CH2CF3��CH2OCH2CF3��SO2CF3��C(CH3)2CH2CH3��C(CH2CH3)3��CH(OCH2CF3)2��CF3��OCH2C(CH3)2F�� CH(OH)CH2OCH2CF3��CH(OCH2CF3)CH2OH��OSO2CF3��Or OCH2CH2OCF3��
The compound of 26. claims 21, whereinPart is:
27. are selected from the compound of following table:
28. pharmaceutical compositions, it comprises compound and pharmaceutically acceptable carrier of claim 1-27 arbitrary.
The compound of 29. claim 1-27 arbitrary is for the preparation of the purposes in the preparation suppressing the Voltage-gated sodium channels in patient or biological products.
The purposes of 30. claims 29, wherein said Voltage-gated sodium channels is NaV1.7.
The compound of 31. claim 1-27 arbitrary is for the preparation of the following disease in treatment experimenter or the purposes in alleviating the medicine of its severity: acute, chronic, nervosa or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, general neurodynia, epilepsy or epilepsy, neurodegenerative illness, psychiatric disorders, anxiety, dysthymia disorders, bipolar disorders, myotony, irregular pulse, dyskinesia, neuroendocrine illness, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, Encelialgia, postherpetic neuralgia, diabetic neuropathy becomes, nerve root pain, sciatica, backache, headache or cervicodynia, serious or intractable pain, nociceptive pain, explosive pain, postoperative pain, cancer pain, apoplexy, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, the angina of pressure or exercise induced, palpitaition, hypertension, migraine or abnormal gastrointestinal are wriggled.
The purposes of 32. claims 31, wherein said medicine is used for the treatment of osteoarthritis pain or alleviates its severity.
The compound of 33. claim 1-27 arbitrary is for the preparation of the following disease in treatment experimenter or the purposes in alleviating the medicine of its severity: femur pain caused by cancer; Non-malignant chronic ostalgia; Rheumatoid arthritis; Osteoarthritis; Spinal canal stenosis; Nervosa low back pain; Nervosa low back pain; Myofascial pain syndrome; Fibromyalgia; Temporomandibular joint (TMJ) pain; Chronic visceral pain, stomachache; Pancreas pain; IBS pain; Chronic and acute headache; Migraine; Tension headache; Chronic and acute neuropathic pain, postherpetic neuralgia; Diabetic neuropathy becomes; HIV-associated neurological disease; Charcot-MarieTooth neuropathy; Heredity esthesioneurosis; Peripheral nerve injury; Pain neuroma; The nearly side of dystopy and distally electric discharge; Radiculopathy; The neuropathic pain of chemotherapy induction; The neuropathic pain that radiotherapy is brought out; Post mastectomy pain; Central pain; Spinal cord injury pain; Post-stroke pain; Thalamic pain; Complicacy regional pain syndrome; Phantom limb pain; Intractable pain; Acute pain, acute postoperative pain; Arthrodynia; Mechanicalness low back pain; Cervicodynia; Tendonitis; Damage/motion pain; Acute Encelialgia, stomachache; Pyelonephritis; Ecphyaditis; Cholecystitis; Intestinal obstruction; Hernia; Pectoralgia, pained; Pelvis pain, renal colic, acute labor pains, produces pain; Cesarean section pain; Acute inflammation, burn and trauma pain; Acute intermittent pain, endometriosis; Acute herpes zoster pain; Sicklemia; Acute pancreatitis; Explosive pain; Mouth face ache; Multiple sclerosis pain; Dysthymia disorders pain; Leprosy pain; Behcets disease pain; Adiposis dolorosa; Phlebitis pain; Guillain-Barre pain; Thigh and movable toe are pain caused; Haglund syndrome; Erythromelalgia; Method cloth Richter scale disease pain; Bladder and urogenital disease; Bladder hyperactivity; Painful bladder syndrome; Interstitial cystitis; Prostatitis; Complicacy regional pain syndrome, I type and II type; Popularity pain, paroxysmal severe pain disease, pruritus, tinnitus or angina bringing out property pain.
The purposes of 34. claims 33, wherein said medicine is used for the treatment of acute flesh skeleton pain or alleviates its severity.
The compound of 35. claim 1-27 arbitrary is for the preparation of the following disease in treatment experimenter or the purposes in alleviating the medicine of its severity: cluster headache, trigeminal neuralgia, sinusitis paranasal sinusitis pain, toothache, the urinary incontinence.
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